Next Article in Journal
A Conserved N-Terminal Di-Arginine Motif Stabilizes Plant DGAT1 and Modulates Lipid Droplet Organization
Previous Article in Journal
Effects of Near-Infrared Diode Laser Irradiation on Pain Relief and Neuropeptide Markers During Experimental Tooth Movement in the Periodontal Ligament Tissues of Rats: A Pilot Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 15
10.3390/ijms26157405
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease

by
Taishi Honda
,
Masahito Kawabori
* and
Miki Fujimura
Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7405; https://doi.org/10.3390/ijms26157405 (registering DOI)
Submission received: 18 June 2025 / Revised: 13 July 2025 / Accepted: 29 July 2025 / Published: 31 July 2025
(This article belongs to the Special Issue Stem Cells Research: Advancing Science and Medicine)
Browse Figures
Review Reports Versions Notes

Abstract

Central nervous system (CNS) disorders present significant therapeutic challenges due to the limited regenerative capacity of neural tissues, resulting in long-term disability for many patients. Consequently, the development of novel therapeutic strategies is urgently warranted. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Recent research has also identified exosomes—small vesicles enclosed by a lipid bilayer, secreted by stem cells—as a key mechanism underlying the therapeutic effects of stem cell therapies, and given their enhanced stability and superior blood–brain barrier permeability compared to the stem cells themselves, exosomes have emerged as a promising alternative treatment for CNS disorders. A key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration. Intracerebral injection can deliver a substantial quantity of stem cells directly to the brain, but it carries the potential risk of inducing additional brain injury. Conversely, intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain, which may compromise the therapeutic efficacy. With advancements in catheter technology, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages. In this comprehensive review, we aim to summarize both basic and clinical research exploring the intra-arterial administration of stem cells and exosomes for the treatment of CNS diseases. Additionally, we will elucidate the underlying therapeutic mechanisms and provide insights into the future potential of this approach.

Graphical Abstract

1. Introduction

Despite the advances of modern medicine, central nervous system (CNS) diseases, including stroke, trauma, psychiatric, and neurodegenerative diseases, are one of the intractable diseases that leave many patients disabled. There is an urgent need to develop a treatment method to treat these diseases. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects, and many clinical trials are currently ongoing to prove their safety and efficacy [1,2,3,4,5]. In recent years, considerable research efforts have also been directed towards elucidating the role of exosomes as a crucial therapeutic mechanism of stem cells. Exosomes, nano-sized vesicles ranging from 40 to 200 nm, are composed of a double lipid-layer membrane and harbor a plethora of molecules, including DNA, mRNA, microRNA (miRNA), and proteins [6]. Stem cell-derived exosomes have exhibited remarkable potential in mitigating central nervous system (CNS) diseases by virtue of their anti-apoptotic, anti-inflammatory, neurogenic, and angiogenic properties [7,8,9,10,11,12,13].
Regardless of their promising nature, a key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration [11]. Intracerebral injection can deliver a substantial quantity of stem cells and exosomes directly to the brain, but it carries the potential risk of inducing additional brain injury. Intrathecal transplantation can also offer a large amount of stem cells and exosomes to the cerebroventricular space, while the efficacy of stem cell engraftment or exosome absorption is limited by the risk of hydrocephalus [14]. Intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain (1–10%), which may compromise the therapeutic efficacy [10,15,16,17]. The intranasal approach is also minimally invasive; however, its absorption rate is not as high as expected (<1%) [13]. Disappointing results from intravenous stem cell transplantation have driven the search for more effective therapeutic strategies to deliver stem cells to the damaged brain [18,19,20,21,22]. In these circumstances, with advancements in catheter technology, especially for treating ischemic stroke through thrombectomy, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages.
In this review, we summarize the intra-arterial administration of stem cells and their exosomes for CNS diseases, focusing on both basic and clinical research to clarify their efficacy and mechanism of action, as well as their limitations and future applications.
A literature search was conducted on PubMed (https://www.ncbi.nlm.nih.gov/pubmed, accessed on 25 February 2025) to identify research articles on intra-arterial stem cell or exosome administration for CNS diseases. The search utilized the keywords “intraarterial”, “stem cell”, “exosome or extracellular vesicle”, and “brain”. The articles included in the search were required to be written in English, relevant to CNS diseases, and specifically focused on stem cells and exosomes, while other articles were excluded. Additionally, we reviewed references cited within the selected papers from the preliminary search. The selection of articles and data collection were performed by one of the authors (T.H.). The collected data encompassed various disease models, cell and exosome sources, animal models, dosage, treatment duration, and labeling methods.

2. Overall Results of IA Transplantation of Stem Cell and Exosome for CNS Disease

A total of 87 articles were chosen that align with the objectives of this review; 71 articles were selected as preclinical studies that used stem cells via intra-arterial treatment (Supplementary Table S1) [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93], 4 articles were selected as preclinical studies that used exosomes focusing on IA treatment (Supplementary Table S2) [94,95,96,97], and 12 articles were selected as clinical studies that used stem cells through IA treatment [98,99,100,101,102,103,104,105,106,107,108,109].

3. Preclinical Studies of Cell Therapy

Among the 71 studies reviewed, the majority (57 articles, 82%) focus on ischemic stroke. The remaining studies investigate traumatic brain injury, glioma, intracerebral hemorrhage, Alzheimer’s disease, Parkinson’s disease, and complication analysis associated with intra-arterial (IA) transplantation. This distribution is attributable to the fact that brain artery obstruction is the primary mechanism underlying ischemic stroke, making it logical to treat both the brain and blood vessels through the same therapeutic route. In this subsection, the authors summarize the preclinical data related to each of these diseases.

3.1. Ischemic Stroke

Ischemic stroke, caused by the occlusion of a brain blood vessel, leads to the deprivation of glucose and oxygen in its downstream branches, emerging as the leading cause of global disability. It is the third most common cause of death (10.7% of all deaths) and the fourth leading cause of Disability-Adjusted Life Years (DALYs) worldwide (5.6% of all DALYs) [110]. At present, standardized treatments, such as thrombectomy and recombinant tissue plasminogen activator (r-tPA) therapy, are implemented during the acute phase (<4.5 h) to re-establish blood flow in the occluded vessel and to salvage the penumbra. However, approximately 50% of the patients will present neurological deficits even after successful recanalization [111]. Consequently, intra-arterial transplantation of stem cells and exosomes is considered a promising approach to mitigate the severity of sequelae.

3.1.1. Cell Sources

The source of stem cells is a critical factor in stem cell therapy (Figure 1, Supplementary Table S1). Of the 57 studies reviewed, 29 studies (51%) utilized human cells, while 28 studies (49%) employed animal allogeneic cells, with 1 study evaluating both human and animal allogeneic cells [51]. A wide range of human cell sources have been explored; 16 studies (52%) used bone marrow-derived mesenchymal stromal cells (BMSCs) or bone marrow-derived mononuclear cells (BMMNCs), 7 studies (22%) used umbilical cord blood-derived mesenchymal stem cells (MSCs), 3 studies (10%) used amnion-derived MSCs, 2 studies (6%) used adipose-derived MSCs and embryonic stem cells (ESC), and 1 study used hematopoietic stem cells, hair follicle stem cells, and induced pluripotent stem cells. In contrast, animal allogeneic cells demonstrated different characteristics. Eleven studies (40%) used BMSC or BMMNC, which are similar to human cells, while another eleven studies (40%) employed neural stem cells (NSCs) or neural crest-derived stem cells, which are derived from fetal brain tissue. The use of fetal brain-derived cells is particularly challenging, as they must be sourced from the fetal brain, which is not readily available for human applications. While most of the studies (42/58; 71%) utilized stem cells alone, some studies modified the cells through pretreatment with various substances, gene induction, and cell purification (Table 1). Interestingly, these modifications can be further categorized into three factors: enhanced neural differentiation [26,32,36,45,50,79,93], improved cell engraftment and migration to the damaged site [38,40,49,78], and the promotion of upregulating growth factor release or anti-inflammatory effects [23,24,85], all of which enhance the efficacy of cell therapy. Although most naïve cells show significant recovery, some studies compared modified cells with naïve cells. However, the modification of stem cells often results in higher labor costs and a lower cell collection yield, and the clinical value of such modifications remains uncertain.
Khabbal et al. compared the engraftment of xenogeneic human cells and allogeneic animal cells using isotope labeling techniques. They found that both cell types were detected in the ischemic brain shortly after transplantation, with radioactivity levels rapidly decreasing during the follow-up periods at 3 and 6 h. Interestingly, the radioactivity of xenogeneic human cells decreased much more rapidly than that of animal cells by 6 h after transplantation, which may be attributed to immune rejection [51]. This finding underscores the need for caution when extrapolating animal data to human studies. Salehi et al. compared neural crest stem cells (NCSCs) and BMSCs, finding that although both cell types exhibited satisfactory recovery, the expression of trophic factors differed significantly between the two. NCSCs expressed BDNF, nestin, Sox10, and doublecortin, while BMSCs expressed GDNF [34]. These findings highlight the importance of trophic factors in the recovery process, and further studies are needed to elucidate the specific trophic factors necessary for optimal recovery. Yamaguchi et al. compared young and old BMSC regarding the functional recovery and found that younger cells exhibited better neurogenesis and angiogenesis, highlighting the difference in cell donor age for recovery [39].

3.1.2. Cell Doses

While the majority of studies provide animal weights in the Methods section, some articles do not. In such cases, we defined the rat weight as 250 g and the mouse weight as 25 g. The amount of cells administered intra-arterially varies widely across studies, ranging from 0.4 to 1333 × 105 cells/kg (Figure 2, Supplementary Table S1). However, a clear trend emerges in which heavier animals receive fewer cells per body weight. Mice tend to receive approximately 200 × 105 cells/kg, rats receive 50 × 105 cells, and dogs receive 10 × 105 cells/kg. This discrepancy may arise from the fact that most animals, regardless of weight, typically receive 1 × 106 cells intra-arterially. There are several reports that focused on the therapeutic effect of the different cell doses. Fukuda et al. compared 0.4 and 36.4 × 105 cells/kg of BMSC against the rat ischemic stroke model and found that both doses showed significant recovery with lower inflammation compared with the control group, and the high-dose group showed a higher mortality rate (39%) compared with the low-dose (27%) and control (33%) groups. They also observed a higher amount of microvessel clogging with the transplanted cells in the high-dose group [56]. When administering higher numbers of cells, there is always concern regarding microvessel obstruction, which can reduce blood flow and compromise recovery. Yavagal et al. compared cerebral blood flow following administration of various cell numbers (2–35 × 105 cells/kg) and concluded that the maximum number of cells that does not compromise blood flow is 3.5 × 105 cells/kg or less [60]. Cui et al. also reported that a lower dose (10 × 105 cells/kg) was superior to higher doses (20 and 40 × 105 cells/kg) in terms of minimizing blood flow reduction [58]. Magnetic resonance (MR) imaging studies also showed that the administration of a smaller number of cells (1 and 8 × 105 cells/kg) resulted in less brain damage compared to a larger dose (26 × 105 cells/kg), with larger doses leading to arterial clogging [44]. On the other hand, Greggio et al. compared 50 and 500 × 105 cells/kg of umbilical cord blood mononuclear cells after perinatal ischemic brain injury and reported that a higher number of cells resulted in better functional recovery and smaller brain damage [59]. Yang et al. also reported that animals receiving 300 × 105 cells/kg of bone marrow-derived mononuclear cells showed better recovery compared to those receiving 10 × 105 cells/kg [70]. Wong et al. reported that interleukin-1a preconditioned MSCs (40 × 105 cells/kg) enabled upregulation of blood flow monitored by Laser speckle imaging 1.5 h after cell transplantation, which they speculated was the role of vascular endothelial growth factor (VEGF) released from conditioned cells. In addition to the number of cells administered, the administration speed is another important factor in minimizing brain damage. When 20 × 105 cells/kg were diluted in 0.5 mL or 1 mL and administered over 3 or 6 min, the denser cell concentration (0.5 mL) with slower injection (6 min) resulted in poorer functional outcomes [58]. Chua et al. also demonstrated that continuous arterial flow in the internal carotid artery during cell transplantation resulted in better recovery compared to when arterial flow ceased. Ge et al. found that smaller cell sizes yielded favorable results, with a 30 μm cell group causing arterial obstruction and acute ischemic damage, while 12 and 17 μm cell groups did not [65]. These findings highlight the importance of avoiding arterial obstruction during cell transplantation. As a result, the optimal dose for human treatment remains unknown; however, developing an optimal method to minimize arterial blood obstruction may be crucial for improving recovery outcomes.

3.1.3. Transplantation Timing

Transplantation timing varies across studies, ranging from immediately after recanalization to day 14 (Figure 3). The most common transplantation timing occurs on day 1, followed by 1–6 h and 2–3 days. Immediate transplantation has become more common in recent years, likely due to the concept of treating patients directly after thrombectomy procedures. However, while thrombectomy has demonstrated that “the faster, the better,” this principle does not appear to apply to cell transplantation. Toyoshima et al. reported that stem cell transplantation at 24 h after recanalization resulted in better functional recovery compared to transplantation at 1 h and 6 h [53]. They also observed that the number of engrafted cells in the brain parenchyma was highest in the 24 h group, compared to the 1 h, 6 h, and 48 h groups. While the exact reason for this remains unclear, the authors speculated that the failure of ultra-early transplantation to show recovery may be due to the fact that the blood–brain barrier (BBB) remains functional up to 4 h after stroke, preventing transplanted cells from integrating into the damaged brain at this early stage [112,113]. Similar findings were reported by other researchers, who also found that transplantation at 24 h was superior to transplantation at 1 h after recanalization [60]. Rosenblum et al. also compared different time points (6 h, 1 day, 3 days, 7 days, and 14 days) of cell transplantation and found that cell engraftment was highest on day 3, followed by day 1, with other time points showing limited engraftment [74]. These results indicate that ultra-early cell administration may not be as beneficial as transplantation during the subacute phase, due to the detrimental environment. Later time points have also been evaluated in several studies. Mitkari et al. showed that both day 2 and day 7 administration resulted in better functional recovery compared to the control group, with the day 7 group showing enhanced angiogenesis at the infarction border [64]. Conversely, Ishizaka et al. reported that transplantation at earlier time points (1, 4, and 7 days) led to superior outcomes, with the 1-day group performing better than the 4-day and 7-day groups [71]. Based on these findings, ultra-early administration of stem cells may not be as beneficial as transplantation during the subacute phase, and optimal timing may be around 24–72 h after recanalization. However, further investigation into the precise mechanisms of action and the development of monitoring technologies is necessary to optimize the therapeutic potential for human clinical applications.

3.1.4. Tracking Transplanted Cells and Visualizing Brain Condition

MR imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), laser Doppler/speckle imaging, and bioluminescence imaging are employed to track the fate of transplanted cells and visualize changes in the host brain (Supplementary Table S1). Through MR imaging, most studies evaluating the fate of transplanted cells have shown successful visualization, particularly in the ischemic core soon after cell transplantation. However, transplanted cells generally do not remain visible for longer than 72 h post-transplantation [32,36,52,82]. Other methodologies showed similar results, that bioluminescence imaging revealed that cells expressing luminescence rapidly decreased to approximately 40% on the next day of transplantation [50]. On the other hand, Andres et al. found that neural stem cells showed constant luminescence up to 48 h after transplantation [78]. The fate of transplanted cells in other organs is also examined by SPECT imaging; while the signal from the brain rapidly decreased 3–6 h after transplantation, the signal increased in the liver, spleen, and kidney [51,76,77]. However, the signal outside of the brain that truly represents live cells remains unknown because radioactive molecules released from dead and depredated cell particles containing radioactive molecules are likely to be captured in these organs. Regarding changes in the host brain, Huang et al. reported that cerebral blood flow (CBF), as evaluated by MR imaging, was upregulated in the cell treatment group at 28 days post-transplantation, with angiogenesis being enhanced [41]. The data was further confirmed by Du et al., who found increasing cerebral perfusion and glucose metabolism observed by SPECT and PET [62]. Bai et al. further reported visualization of the corticospinal tract after cell transplantation, showing that cell treatment successfully restored it, which was visualized through fractional anisotropy and diffusion tensor imaging [49]. Development of imaging technologies will enable a better understanding of the cells’ fate and the recovery mechanisms of the host brain.

3.1.5. Mechanisms of Recovery

The intra-arterial transplantation of stem cells induces multiple recovery mechanisms, which can be classified into regeneration and damage reduction (Table 2). Regeneration encompasses neurogenesis, synaptogenesis, and angiogenesis, while damage reduction includes anti-inflammatory effects, anti-oxidative stress, anti-apoptotic effects, anti-ferroptotic effects, neuroprotection, endoplasmic reticulum protection, BBB protection, and exosome release.
Neurogenesis is one of the most important mechanisms for functional recovery. In addition to the direct differentiation of transplanted cells into neuronal cells [35,45,69], accelerated endogenous neurogenesis has also been observed. Transplanted cells enhance the maturation and migration of immature neural cells in the subventricular zone (SVZ) to the peri-damaged area [23,52,91]. Synaptogenesis is also observed, with endogenous neural cells demonstrating neurite and axon extension following stem cell transplantation [25]. Angiogenesis can occur either through the direct differentiation of transplanted cells into vessel-forming cells or by enhancing endogenous vessel formation, primarily through vascular endothelial growth factor (VEGF) released by the transplanted cells [23,26,41]. Angiogenic activity has been shown to restore not only histological vessel density but also cerebral blood circulation, as evidenced by brain perfusion studies around the peri-damaged area [24]. Interestingly, while angiogenesis is upregulated throughout the brain, distinct angiogenic gene expression profiles have been observed between the striatum, cortex, and hippocampus, indicating the complex angiogenic properties in different brain regions [25,34]. Cell modification with overexpression of very late antigen-4 (VLA-4) or neurogenin-1 increases cell adhesion to endothelial cells. This underscores the importance of the “stem cell-endothelial cell” adhesion in recovery [36,40].
Since most studies focus on acute-stage stem cell transplantation, damage reduction also plays a critical role in transplanted cell therapy. Stem cells mitigate local inflammation in the ischemic brain [27], as well as reduce oxidative stress [93], apoptosis [66], and ferroptosis [93] at the site of injury. Additional reports have demonstrated that specific brain components, such as neurons [27], the endoplasmic reticulum [30], and BBB [28] are protected by stem cell transplantation. Detailed functional analyses have revealed that inflammation is modulated by acid-sensing ion channels [29], apoptosis is alleviated by calcineurin released from transplanted cells [37], and BBB is preserved via protein kinase C delta (PKCδ)/aquaporin-4 (AQP4) pathway [28]. The upregulation of exosome release in the cell-treated group has been reported; however, their role in the brain remains incompletely understood and requires further investigation [23].

3.2. Traumatic Injury

Traumatic brain injury (TBI) affects over 50 million individuals worldwide each year, and a significant proportion of these patients experience long-term disabilities, as evidenced by the stagnation in return-to-work rates over the past 50 years [3]. Stem cell therapy is regarded as a promising approach to ameliorate functional deficits, and numerous basic and clinical trials have been conducted through intracerebral or intravenous transplantation [3]. Recently, following favorable results from our clinical trial, stem cell products employing intracerebral transplantation have been approved in Japan [114,115]. As such, the number of studies utilizing intra-arterial stem cell transplantation for TBI remains limited (Supplementary Table S1) [57,67,75,84]. The findings from these studies are similar to those of ischemic stroke research, where 5–25 × 105 cells/kg of human or rat BMSC or NSC were injected 1–14 days post-TBI. While the data appear promising, further research is required to fully elucidate the therapeutic potential of stem cell therapy for TBI via intra-arterial transplantation.

3.3. Intracerebral Hemorrhage (ICH)

Due to the lack of effective therapies, stem cell transplantation can be a promising treatment modality for intracerebral hemorrhage (ICH). Similarly to traumatic brain injury, both intracerebral and intravenous stem cell transplantations have been the focus of research. Several clinical trials, including ours, are currently ongoing [1,2]. We identified only one study that utilized intra-arterial stem cell transplantation for ICH. Seyfried et al. reported that the injection of 10 × 105 cells/kg of human BMSC one day after ICH, in combination with mannitol administration, successfully attenuated functional deficits by promoting neurogenesis [90].

3.4. Glioma

Malignant glioma is the most common and life-threatening primary brain malignancy in adults, with a median survival time of only 14 months, even with modern multidisciplinary treatments, including surgical resection followed by radiation and chemotherapy [116]. In this context, effective drug delivery to glioma cells is critical, and the ability of mesenchymal stem cells (MSCs) to accumulate in inflammatory regions presents a promising avenue for drug vector therapy. Oncolytic viruses, which have shown promising results in clinical trials [117], are being considered as part of this therapeutic approach. Therefore, MSCs infected with oncolytic viruses are emerging as a potential treatment strategy [117]. We identified four studies that focused on the treatment of glioma using virus/drug combinations for intra-arterial stem cell transplantation. In these studies, MSCs infected with oncolytic viruses successfully accumulated in the glioma tissue, but not in the healthy brain, when transplanted via the carotid artery. These cells inhibited tumor growth and increased survival time in animal models [80,86,118]. Conversely, MSCs overexpressing interferon gamma did not yield therapeutic benefits [33]. These findings suggest that transfected MSCs, which deliver infectious material, may have a higher potential for tumor treatment compared to the simple delivery of proteins.

3.5. Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting over 55 million people worldwide, primarily in older adults. It causes memory loss, cognitive decline, and behavioral changes. Current treatments primarily focus on symptom management, utilizing cholinesterase inhibitors and emerging therapies targeting amyloid plaques, although no cure has been found. A single report investigating intra-arterial stem cell transplantation for AD has been published, though the results were unfavorable [92]. Since the BBB is not easily penetrable in AD, unlike in the acute and subacute phases of stroke or traumatic brain injury (TBI), the use of BBB-opening agents such as mannitol may prove beneficial and should be considered in future studies. Furthermore, due to the unlimited therapeutic window, multiple injections of stem cells or exosomes may be a good option for neurodegenerative diseases.

3.6. Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder that affects approximately 10 million individuals worldwide. It is characterized by tremors, rigidity, bradykinesia, and postural instability. Although no cure exists, treatments such as levodopa and dopamine agonists help manage symptoms, and deep brain stimulation is used in advanced cases. Cerri et al. reported that mesenchymal stem cells (MSCs) pretreated with mannitol facilitated their passage into the damaged striatum and nigra. While functional recovery was observed with this approach, no modification of damaged brain cells was detected, suggesting that the therapeutic effect may be limited [55].

3.7. Safety Issues of IA Transplantation

Two reports have specifically focused on the safety issues related to intra-arterial transplantation, which is critical for enhancing its clinical application [58,65]. Cui et al. compared different cell doses and infusion speeds, concluding that slow injection of larger cell doses may lead to worse functional recovery due to the formation of microthrombi during the transplantation process. They suggested that dispersing cells more effectively might be necessary to reduce vascular obstruction [58]. Similarly, Ge et al. investigated the relationship between stem cell size and vascular obstruction, finding that smaller cell sizes (12–18 µm) caused less vessel obstruction and resulted in better functional recovery compared to larger cells (30 µm) [65]. They reported that 3D cell culture promoted smaller cell sizes compared to 2D culture, potentially reducing complications. Cell senescence has been shown to affect cell size, and supplementing culture media can influence this process. Our group recently discovered that human platelet lysate, compared to fetal bovine serum, resulted in better cell expansion rates and less senescence of smaller cell size, offering a potential improvement for stem cell culture conditions [119].

4. Preclinical Studies of Exosome Therapy

Recent advancements have highlighted that stem cell-derived exosomes may represent a pivotal therapeutic mechanism [7,8,9]. Exosomes are small vesicles (40–200 nm) released by stem cells and can be extracted from the supernatant of the culture medium. They encapsulate a variety of molecules, including DNA, mRNA, microRNA (miRNA), and proteins [6], all of which can be transferred into target cells, thereby providing therapeutic benefits in mitigating neurological diseases [7,8,9]. Furthermore, exosomes offer several advantages over traditional stem cell therapy, including high preservation capacity, low immunogenicity, the ability to cross the BBB, and the potential for drug encapsulation. As a result, exosomes are increasingly considered a promising alternative therapeutic approach [120]. Due to their novelty, the body of research on intra-arterial exosome infusion remains limited. (Supplementary Table S2) In the context of ischemic stroke, exosomes have been demonstrated to promote neurite outgrowth and exert anti-inflammatory effects. Xin et al. reported the efficacy of allogeneic BMSC-derived exosomes, in which BMSCs are overexpressed with microRNA (mir) 133b. They intra-arterially transplanted 3 × 1011 exosome particles suspended in 0.5 mL saline 24 h after middle cerebral artery occlusion. The exosomes enriched with miR-133b promoted neurovascular plasticity and achieved better functional recovery [94]. Similarly, traumatic brain injury was successfully attenuated by BMSC-derived exosomes [96]. Dabrowska et al. demonstrated that human BMSC-derived exosomes (1.3 × 109 particles/1 mL) achieved better anti-inflammatory effect compared with BMSC itself. However, further evaluations of the therapeutic difference in exosomes and MSCs are not fully elucidated [96]. Lysosomal storage disorder is also evaluated with intra-arterial exosome transplantation. Seras-Franzoso et al. reported that mammalian cells overexpressing alpha-galactosidase A (GLA) successfully secrete exosomes containing abundant GLA. Exosomes were intra-arterially transplanted against GLA-deficient animals, and exosomes were rapidly uptaken, with approximately 7.5% of transplanted exosomes reaching the brain parenchyma and showing good enzyme activity in the brain [95]. Shi et al. further modified exosomes with a neuronal targeting peptide (rabies virus glycoprotein 29; RVG29), which facilitates cell delivery to the neuronal cells. Modified exosomes successfully enter the brain and attenuate apoptotic activity by affecting the p38/ERK signaling pathway [97]. Although further evaluation is necessary, intra-arterial exosome transplantation seems to be a promising therapeutic approach for brain disease.

5. Clinical Trials Using Stem Cell and Exosome via Intra-Arterial Transplantation

Twelve articles have investigated intra-arterial stem cell transplantation, while no clinical trials have been published on intra-arterial exosome transplantation [98,99,100,101,102,103,104,105,106,107,108,109]. The detailed data are presented in Table 3. Consistent with animal studies, the majority of these clinical trials focused on ischemic stroke, with additional studies addressing intractable diseases such as multiple system atrophy, epilepsy, and progressive supranuclear palsy. Unlike basic research, the clinical trials predominantly used autologous bone marrow mononuclear cells (BMMNCs), followed by autologous BMSC, likely due to safety concerns associated with early-phase clinical studies, which have prompted researchers to hesitate in using allogeneic cells. Nevertheless, to enable broader global distribution of stem cell products, the use of allogeneic stem cells remains a critical consideration. The cell doses administered in the trials varied, ranging from 3 to 160 × 105 cells/kg, which is consistent with data from animal experiments as previously reported. Most studies report no serious adverse events associated with intra-arterial transplantation, although Giordano et al. observed asymptomatic ischemic signs in 85% (6 out of 7) of patients, which should not be overlooked [107]. Regarding ischemic stroke, while early single-arm clinical trials have shown favorable outcomes [99,102,104,109], large randomized trials have failed to demonstrate statistically significant differences in recovery [100,101,106,108]. In this context, Bhatia et al. reported a marginal trend toward recovery (p = 0.07), suggesting potential for future improvements. Notably, the transplantation cell dose in Bhatia’s study (83 × 105 cells/kg) was higher than in other groups, indicating the possibility that a higher optimal cell dose for BMMNC intra-arterial transplantation may be necessary. Lee et al. and Chung et al., from the same research group, evaluated BMSC transplantation for multiple system atrophy and found that higher and medium-dose groups (6 or 9 × 105 cells/kg) slowed disease progression compared to the low-dose group (3 × 105 cells/kg), showing promise given the typically poor prognosis of this disease [98,103]. However, this research did not follow any basic studies concerning intra-arterial transplantation for this disease, and while the difficulty in mimicking animal models for rare diseases is acknowledged, a more detailed evaluation is essential before proceeding with clinical trials. Consequently, clinical trials employing intra-arterial stem cell transplantation remain in the early stages, and further, more refined trial designs are needed to validate their efficacy as demonstrated in animal models.

6. Conclusions and Future Direction

Intra-arterial stem cell/exosome transplantation offers several advantages over other transplantation approaches. Advances in catheter technology and technique will enhance the safety of this method, while a deeper understanding of the properties of stem cells and exosomes will facilitate improved functional outcomes for CNS diseases. Further evaluation of optimal cell sources, doses, timing, tracking methods, and underlying mechanisms is essential for the development of novel therapeutic modalities.

Supplementary Materials

The supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26157405/s1.

Funding

This study was supported by KAKENHI under grant numbers 23K08535 and 22K09274.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Kawabori, M.; Shichinohe, H.; Kahata, K.; Miura, A.; Maeda, K.; Ito, Y.M.; Mukaino, M.; Kogawa, R.; Nakamura, K.; Gotoh, S.; et al. Phase I/II trial of intracerebral transplantation of autologous bone marrow stem cells combined with recombinant peptide scaffold for patients with chronic intracerebral haemorrhage: A study protocol. BMJ Open 2024, 14, e083959. [Google Scholar] [CrossRef]
  2. Takamiya, S.; Kawabori, M.; Fujimura, M. Stem Cell Therapies for Intracerebral Hemorrhage: Review of Preclinical and Clinical Studies. Cell Transplant. 2023, 32, 9636897231158153. [Google Scholar] [CrossRef]
  3. Kawabori, M.; Chida, D.; Nejadnik, B.; Stonehouse, A.H.; Okonkwo, D.O. Cell therapies for acute and chronic traumatic brain injury. Curr. Med. Res. Opin. 2022, 38, 2183–2189. [Google Scholar] [CrossRef] [PubMed]
  4. Yamazaki, K.; Kawabori, M.; Seki, T.; Houkin, K. Clinical Trials of Stem Cell Treatment for Spinal Cord Injury. Int. J. Mol. Sci. 2020, 21, 3994. [Google Scholar] [CrossRef]
  5. Kawabori, M.; Shichinohe, H.; Kuroda, S.; Houkin, K. Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke. Int. J. Mol. Sci. 2020, 21, 7380. [Google Scholar] [CrossRef] [PubMed]
  6. Kosaka, N.; Iguchi, H.; Ochiya, T. Circulating microRNA in body fluid: A new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010, 101, 2087–2092. [Google Scholar] [CrossRef] [PubMed]
  7. Tkach, M.; Thery, C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell 2016, 164, 1226–1232. [Google Scholar] [CrossRef]
  8. Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Thery, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 2019, 21, 9–17. [Google Scholar] [CrossRef]
  9. Valadi, H.; Ekstrom, K.; Bossios, A.; Sjostrand, M.; Lee, J.J.; Lotvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659. [Google Scholar] [CrossRef]
  10. Morishima, Y.; Kawabori, M.; Yamazaki, K.; Takamiya, S.; Yamaguchi, S.; Nakahara, Y.; Senjo, H.; Hashimoto, D.; Masuda, S.; Fujioka, Y.; et al. Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p. Int. J. Mol. Sci. 2024, 25, 2406. [Google Scholar] [CrossRef]
  11. Gotoh, S.; Kawabori, M.; Fujimura, M. Intranasal administration of stem cell-derived exosomes for central nervous system diseases. Neural Regen. Res. 2024, 19, 1249–1255. [Google Scholar] [CrossRef]
  12. Ikeda, T.; Kawabori, M.; Zheng, Y.; Yamaguchi, S.; Gotoh, S.; Nakahara, Y.; Yoshie, E.; Fujimura, M. Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury. Pharmaceutics 2024, 16, 446. [Google Scholar] [CrossRef]
  13. Gotoh, S.; Kawabori, M.; Yamaguchi, S.; Nakahara, Y.; Yoshie, E.; Konno, K.; Mizuno, Y.; Fujioka, Y.; Ohba, Y.; Kuge, Y.; et al. Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage. Exp. Neurol. 2025, 386, 115143. [Google Scholar] [CrossRef]
  14. Stoker, T.B.; Andresen, K.E.R.; Barker, R.A. Hydrocephalus Complicating Intrathecal Antisense Oligonucleotide Therapy for Huntington’s Disease. Mov. Disord. 2021, 36, 263–264. [Google Scholar] [CrossRef]
  15. Kawabori, M.; Kuroda, S.; Sugiyama, T.; Ito, M.; Shichinohe, H.; Houkin, K.; Kuge, Y.; Tamaki, N. Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: An optical imaging study. Neuropathology 2012, 32, 217–226. [Google Scholar] [CrossRef] [PubMed]
  16. Arbab, A.S.; Thiffault, C.; Navia, B.; Victor, S.J.; Hong, K.; Zhang, L.; Jiang, Q.; Varma, N.R.; Iskander, A.; Chopp, M. Tracking of In-111-labeled human umbilical tissue-derived cells (hUTC) in a rat model of cerebral ischemia using SPECT imaging. BMC Med. Imaging 2012, 12, 33. [Google Scholar] [CrossRef] [PubMed]
  17. Valeri, A.; Mazzon, E. State of the Art and Future of Stem Cell Therapy in Ischemic Stroke: Why Don’t We Focus on Their Administration? Bioengineering 2023, 10, 118. [Google Scholar] [CrossRef] [PubMed]
  18. Houkin, K.; Osanai, T.; Uchiyama, S.; Minematsu, K.; Taguchi, A.; Maruichi, K.; Niiya, Y.; Asaoka, K.; Kuga, Y.; Takizawa, K.; et al. Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial. JAMA Neurol. 2024, 81, 154–162. [Google Scholar] [CrossRef]
  19. Niizuma, K.; Osawa, S.I.; Endo, H.; Izumi, S.I.; Ataka, K.; Hirakawa, A.; Iwano, M.; Tominaga, T. Randomized placebo-controlled trial of CL2020, an allogenic muse cell-based product, in subacute ischemic stroke. J. Cereb. Blood Flow Metab. 2023, 43, 2029–2039. [Google Scholar] [CrossRef]
  20. Prasad, K.; Sharma, A.; Garg, A.; Mohanty, S.; Bhatnagar, S.; Johri, S.; Singh, K.K.; Nair, V.; Sarkar, R.S.; Gorthi, S.P.; et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 2014, 45, 3618–3624. [Google Scholar] [CrossRef]
  21. Hess, D.C.; Wechsler, L.R.; Clark, W.M.; Savitz, S.I.; Ford, G.A.; Chiu, D.; Yavagal, D.R.; Uchino, K.; Liebeskind, D.S.; Auchus, A.P.; et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017, 16, 360–368. [Google Scholar] [CrossRef]
  22. Jaillard, A.; Hommel, M.; Moisan, A.; Zeffiro, T.A.; Favre-Wiki, I.M.; Barbieux-Guillot, M.; Vadot, W.; Marcel, S.; Lamalle, L.; Grand, S.; et al. Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: A Randomized Clinical Trial. Transl. Stroke Res. 2020, 11, 910–923. [Google Scholar] [CrossRef]
  23. Lee, J.Y.; Cho, J.; D’Egidio, F.; Vignon, C.; Streefkerk, H.; de Kalbermatten, M.; Garitaonandia, I.; Borlongan, C.V. Probing Multiple Transplant Delivery Routes of CD+34 Stem Cells for Promoting Behavioral and Histological Benefits in Experimental Ischemic Stroke. Stem Cells Transl. Med. 2024, 13, 177–190. [Google Scholar] [CrossRef] [PubMed]
  24. Wong, R.; Smith, C.J.; Allan, S.M.; Pinteaux, E. Preconditioning with interleukin-1 alpha is required for the neuroprotective properties of mesenchymal stem cells after ischemic stroke in mice. J. Cereb. Blood Flow Metab. 2023, 43, 2040–2048. [Google Scholar] [CrossRef] [PubMed]
  25. Karimi-Haghighi, S.; Pandamooz, S.; Jurek, B.; Fattahi, S.; Safari, A.; Azarpira, N.; Dianatpour, M.; Hooshmandi, E.; Bayat, M.; Owjfard, M.; et al. From Hair to the Brain: The Short-Term Therapeutic Potential of Human Hair Follicle-Derived Stem Cells and Their Conditioned Medium in a Rat Model of Stroke. Mol. Neurobiol. 2023, 60, 2587–2601. [Google Scholar] [CrossRef]
  26. Cherkashova, E.; Namestnikova, D.; Leonov, G.; Gubskiy, I.; Sukhinich, K.; Melnikov, P.; Chekhonin, V.; Yarygin, K.; Goldshtein, D.; Salikhova, D. Comparative study of the efficacy of intra-arterial and intravenous transplantation of human induced pluripotent stem cells-derived neural progenitor cells in experimental stroke. PeerJ 2023, 11, e16358. [Google Scholar] [CrossRef]
  27. Sarmah, D.; Datta, A.; Kaur, H.; Kalia, K.; Borah, A.; Rodriguez, A.M.; Yavagal, D.R.; Bhattacharya, P. Sirtuin-1—Mediated NF-kappaB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke. Stem Cell Rev. Rep. 2022, 18, 821–838. [Google Scholar] [CrossRef]
  28. Datta, A.; Sarmah, D.; Kaur, H.; Chaudhary, A.; Mounica, K.L.; Kalia, K.; Borah, A.; Yavagal, D.R.; Bhattacharya, P. Post-stroke Impairment of the Blood-Brain Barrier and Perifocal Vasogenic Edema Is Alleviated by Endovascular Mesenchymal Stem Cell Administration: Modulation of the PKCdelta/MMP9/AQP4-Mediated Pathway. Mol. Neurobiol. 2022, 59, 2758–2775. [Google Scholar] [CrossRef] [PubMed]
  29. Vats, K.; Sarmah, D.; Datta, A.; Saraf, J.; Kaur, H.; Pravalika, K.; Wanve, M.; Kalia, K.; Borah, A.; Dave, K.R.; et al. Intra-arterial Stem Cell Therapy Diminishes Inflammasome Activation After Ischemic Stroke: A Possible Role of Acid Sensing Ion Channel 1a. J. Mol. Neurosci. 2021, 71, 419–426. [Google Scholar] [CrossRef] [PubMed]
  30. Kaur, H.; Sarmah, D.; Veeresh, P.; Datta, A.; Kalia, K.; Borah, A.; Yavagal, D.R.; Bhattacharya, P. Endovascular Stem Cell Therapy Post Stroke Rescues Neurons from Endoplasmic Reticulum Stress-Induced Apoptosis by Modulating Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling. ACS Chem. Neurosci. 2021, 12, 3745–3759. [Google Scholar] [CrossRef]
  31. Gubskiy, I.L.; Namestnikova, D.D.; Sukhinich, K.K.; Revkova, V.A.; Melnikov, P.A.; Gubsky, L.V.; Chekhonin, V.P.; Yarygin, K.N. MRI-Based and Histologically Verified 3D Modeling of Spatial Distribution of Intra-Arterially Transplanted Cells in Rat Brain. Bull. Exp. Biol. Med. 2021, 171, 517–522. [Google Scholar] [CrossRef]
  32. Namestnikova, D.D.; Gubskiy, I.L.; Revkova, V.A.; Sukhinich, K.K.; Melnikov, P.A.; Gabashvili, A.N.; Cherkashova, E.A.; Vishnevskiy, D.A.; Kurilo, V.V.; Burunova, V.V.; et al. Intra-Arterial Stem Cell Transplantation in Experimental Stroke in Rats: Real-Time MR Visualization of Transplanted Cells Starting With Their First Pass Through the Brain With Regard to the Therapeutic Action. Front. Neurosci. 2021, 15, 641970. [Google Scholar] [CrossRef]
  33. Mao, J.; Cao, M.; Zhang, F.; Zhang, J.; Duan, X.; Lu, L.; Yang, Z.; Zhang, X.; Zhu, W.; Zhang, Q.; et al. Peritumoral administration of IFNbeta upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model. J. Immunother. Cancer 2020, 8, e000164. [Google Scholar] [CrossRef] [PubMed]
  34. Salehi, M.S.; Pandamooz, S.; Safari, A.; Jurek, B.; Tamadon, A.; Namavar, M.R.; Dianatpour, M.; Dargahi, L.; Azarpira, N.; Fattahi, S.; et al. Epidermal neural crest stem cell transplantation as a promising therapeutic strategy for ischemic stroke. CNS Neurosci. Ther. 2020, 26, 670–681. [Google Scholar] [CrossRef]
  35. Kondori, B.J.; Asadi, M.H.; Bahadoran, H.; Yari, A.; Sarshoori, J.R. Intra-arterial transplantation of neural stem cells improve functional recovery after transient ischemic stroke in adult rats. Bratisl. Lek. Listy 2020, 121, 8–13. [Google Scholar] [CrossRef] [PubMed]
  36. Kim, G.H.; Subash, M.; Yoon, J.S.; Jo, D.; Han, J.; Hong, J.M.; Kim, S.S.; Suh-Kim, H. Neurogenin-1 Overexpression Increases the Therapeutic Effects of Mesenchymal Stem Cells through Enhanced Engraftment in an Ischemic Rat Brain. Int. J. Stem Cells 2020, 13, 127–141. [Google Scholar] [CrossRef] [PubMed]
  37. Saraf, J.; Sarmah, D.; Vats, K.; Kaur, H.; Pravalika, K.; Wanve, M.; Kalia, K.; Borah, A.; Dave, K.R.; Yavagal, D.R.; et al. Intra-arterial stem cell therapy modulates neuronal calcineurin and confers neuroprotection after ischemic stroke. Int. J. Neurosci. 2019, 129, 1039–1044. [Google Scholar] [CrossRef]
  38. Andrzejewska, A.; Nowakowski, A.; Grygorowicz, T.; Dabrowska, S.; Orzel, J.; Walczak, P.; Lukomska, B.; Janowski, M. Single-cell, high-throughput analysis of cell docking to vessel wall. J. Cereb. Blood Flow Metab. 2019, 39, 2308–2320. [Google Scholar] [CrossRef]
  39. Yamaguchi, S.; Horie, N.; Satoh, K.; Ishikawa, T.; Mori, T.; Maeda, H.; Fukuda, Y.; Ishizaka, S.; Hiu, T.; Morofuji, Y.; et al. Age of donor of human mesenchymal stem cells affects structural and functional recovery after cell therapy following ischaemic stroke. J. Cereb. Blood Flow Metab. 2018, 38, 1199–1212. [Google Scholar] [CrossRef]
  40. Jablonska, A.; Shea, D.J.; Cao, S.; Bulte, J.W.; Janowski, M.; Konstantopoulos, K.; Walczak, P. Overexpression of VLA-4 in glial-restricted precursors enhances their endothelial docking and induces diapedesis in a mouse stroke model. J. Cereb. Blood Flow Metab. 2018, 38, 835–846. [Google Scholar] [CrossRef]
  41. Huang, L.; Liu, Y.; Lu, J.; Cerqueira, B.; Misra, V.; Duong, T.Q. Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function. Stem Cell Res. Ther. 2017, 8, 74. [Google Scholar] [CrossRef]
  42. Zhang, H.L.; Xie, X.F.; Xiong, Y.Q.; Liu, S.M.; Hu, G.Z.; Cao, W.F.; Wu, X.M. Comparisons of the therapeutic effects of three different routes of bone marrow mesenchymal stem cell transplantation in cerebral ischemic rats. Brain Res. 2018, 1680, 143–154. [Google Scholar] [CrossRef]
  43. Huang, H.; Lin, F.; Jiang, J.; Chen, Y.; Mei, A.; Zhu, P. Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke. Stem Cell Res. Ther. 2017, 8, 223. [Google Scholar] [CrossRef]
  44. Grudzenski, S.; Baier, S.; Ebert, A.; Pullens, P.; Lemke, A.; Bieback, K.; Dijkhuizen, R.M.; Schad, L.R.; Alonso, A.; Hennerici, M.G.; et al. The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate. Stem Cell Res. Ther. 2017, 8, 96. [Google Scholar] [CrossRef]
  45. Shin, D.H.; Kim, G.H.; Lee, J.S.; Joo, I.S.; Suh-Kim, H.; Kim, S.S.; Hong, J.M. Comparison of MSC-Neurogenin1 administration modality in MCAO rat model. Transl. Neurosci. 2016, 7, 164–172. [Google Scholar] [CrossRef]
  46. Ding, J.; Zhao, Z.; Wang, C.; Wang, C.X.; Li, P.C.; Qian, C.; Teng, G.J. Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model. Brain Res. 2016, 1642, 209–218. [Google Scholar] [CrossRef] [PubMed]
  47. Cai, Q.; Chen, Z.; Kong, D.K.; Wang, J.; Xu, Z.; Liu, B.; Chen, Q.; Zhou, J. Novel microcatheter-based intracarotid delivery approach for MCAO/R mice. Neurosci. Lett. 2015, 597, 127–131. [Google Scholar] [CrossRef] [PubMed]
  48. Doeppner, T.R.; Kaltwasser, B.; Teli, M.K.; Sanchez-Mendoza, E.H.; Kilic, E.; Bahr, M.; Hermann, D.M. Post-stroke transplantation of adult subventricular zone derived neural progenitor cells—A comprehensive analysis of cell delivery routes and their underlying mechanisms. Exp. Neurol. 2015, 273, 45–56. [Google Scholar] [CrossRef]
  49. Bai, Y.Y.; Wang, L.; Chang, D.; Zhao, Z.; Lu, C.Q.; Wang, G.; Ju, S. Synergistic Effects of Transplanted Endothelial Progenitor Cells and RWJ 67657 in Diabetic Ischemic Stroke Models. Stroke 2015, 46, 1938–1946. [Google Scholar] [CrossRef]
  50. Rosenblum, S.; Smith, T.N.; Wang, N.; Chua, J.Y.; Westbroek, E.; Wang, K.; Guzman, R. BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery After Transplantation in Hypoxic-Ischemic Stroke. Cell Transplant. 2015, 24, 2449–2461. [Google Scholar] [CrossRef] [PubMed]
  51. Khabbal, J.; Kerkela, E.; Mitkari, B.; Raki, M.; Nystedt, J.; Mikkonen, V.; Bergstrom, K.; Laitinen, S.; Korhonen, M.; Jolkkonen, J. Differential Clearance of Rat and Human Bone Marrow-Derived Mesenchymal Stem Cells From the Brain After Intra-arterial Infusion in Rats. Cell Transplant. 2015, 24, 819–828. [Google Scholar] [CrossRef] [PubMed]
  52. Oh, S.H.; Choi, C.; Chang, D.J.; Shin, D.A.; Lee, N.; Jeon, I.; Sung, J.H.; Lee, H.; Hong, K.S.; Ko, J.J.; et al. Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells. Cytotherapy 2015, 17, 1090–1103. [Google Scholar] [CrossRef]
  53. Toyoshima, A.; Yasuhara, T.; Kameda, M.; Morimoto, J.; Takeuchi, H.; Wang, F.; Sasaki, T.; Sasada, S.; Shinko, A.; Wakamori, T.; et al. Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms. PLoS ONE 2015, 10, e0127302. [Google Scholar] [CrossRef]
  54. Mitkari, B.; Kerkela, E.; Nystedt, J.; Korhonen, M.; Jolkkonen, J. Unexpected complication in a rat stroke model: Exacerbation of secondary pathology in the thalamus by subacute intraarterial administration of human bone marrow-derived mesenchymal stem cells. J. Cereb. Blood Flow Metab. 2015, 35, 363–366. [Google Scholar] [CrossRef] [PubMed]
  55. Cerri, S.; Greco, R.; Levandis, G.; Ghezzi, C.; Mangione, A.S.; Fuzzati-Armentero, M.T.; Bonizzi, A.; Avanzini, M.A.; Maccario, R.; Blandini, F. Intracarotid Infusion of Mesenchymal Stem Cells in an Animal Model of Parkinson’s Disease, Focusing on Cell Distribution and Neuroprotective and Behavioral Effects. Stem Cells Transl. Med. 2015, 4, 1073–1085. [Google Scholar] [CrossRef]
  56. Fukuda, Y.; Horie, N.; Satoh, K.; Yamaguchi, S.; Morofuji, Y.; Hiu, T.; Izumo, T.; Hayashi, K.; Nishida, N.; Nagata, I. Intra-arterial transplantation of low-dose stem cells provides functional recovery without adverse effects after stroke. Cell Mol. Neurobiol. 2015, 35, 399–406. [Google Scholar] [CrossRef]
  57. Silachev, D.N.; Plotnikov, E.Y.; Babenko, V.A.; Danilina, T.I.; Zorov, L.D.; Pevzner, I.B.; Zorov, D.B.; Sukhikh, G.T. Intra-Arterial Administration of Multipotent Mesenchymal Stromal Cells Promotes Functional Recovery of the Brain After Traumatic Brain Injury. Bull. Exp. Biol. Med. 2015, 159, 528–533. [Google Scholar] [CrossRef]
  58. Cui, L.L.; Kerkela, E.; Bakreen, A.; Nitzsche, F.; Andrzejewska, A.; Nowakowski, A.; Janowski, M.; Walczak, P.; Boltze, J.; Lukomska, B.; et al. The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity. Stem Cell Res. Ther. 2015, 6, 11. [Google Scholar] [CrossRef] [PubMed]
  59. Greggio, S.; de Paula, S.; Azevedo, P.N.; Venturin, G.T.; Dacosta, J.C. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in neonatal hypoxic-ischemic rats. Life Sci. 2014, 96, 33–39. [Google Scholar] [CrossRef]
  60. Yavagal, D.R.; Lin, B.; Raval, A.P.; Garza, P.S.; Dong, C.; Zhao, W.; Rangel, E.B.; McNiece, I.; Rundek, T.; Sacco, R.L.; et al. Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS ONE 2014, 9, e93735. [Google Scholar] [CrossRef]
  61. Du, G.; Liu, Y.; Dang, M.; Zhu, G.; Su, R.; Fan, Y.; Tan, Z.; Wang, L.X.; Fang, J. Comparison of administration routes for adipose-derived stem cells in the treatment of middle cerebral artery occlusion in rats. Acta Histochem. 2014, 116, 1075–1084. [Google Scholar] [CrossRef] [PubMed]
  62. Du, S.; Guan, J.; Mao, G.; Liu, Y.; Ma, S.; Bao, X.; Gao, J.; Feng, M.; Li, G.; Ma, W.; et al. Intra-arterial delivery of human bone marrow mesenchymal stem cells is a safe and effective way to treat cerebral ischemia in rats. Cell Transplant. 2014, 23 (Suppl. 1), S73–S82. [Google Scholar] [CrossRef]
  63. Karlupia, N.; Manley, N.C.; Prasad, K.; Schafer, R.; Steinberg, G.K. Intraarterial transplantation of human umbilical cord blood mononuclear cells is more efficacious and safer compared with umbilical cord mesenchymal stromal cells in a rodent stroke model. Stem Cell Res. Ther. 2014, 5, 45. [Google Scholar] [CrossRef]
  64. Mitkari, B.; Nitzsche, F.; Kerkela, E.; Kuptsova, K.; Huttunen, J.; Nystedt, J.; Korhonen, M.; Jolkkonen, J. Human bone marrow mesenchymal stem/stromal cells produce efficient localization in the brain and enhanced angiogenesis after intra-arterial delivery in rats with cerebral ischemia, but this is not translated to behavioral recovery. Behav. Brain Res. 2014, 259, 50–59. [Google Scholar] [CrossRef]
  65. Ge, J.; Guo, L.; Wang, S.; Zhang, Y.; Cai, T.; Zhao, R.C.; Wu, Y. The size of mesenchymal stem cells is a significant cause of vascular obstructions and stroke. Stem Cell Rev. Rep. 2014, 10, 295–303. [Google Scholar] [CrossRef]
  66. Guo, L.; Ge, J.; Zhou, Y.; Wang, S.; Zhao, R.C.; Wu, Y. Three-dimensional spheroid-cultured mesenchymal stem cells devoid of embolism attenuate brain stroke injury after intra-arterial injection. Stem Cells Dev. 2014, 23, 978–989. [Google Scholar] [CrossRef] [PubMed]
  67. Okuma, Y.; Wang, F.; Toyoshima, A.; Kameda, M.; Hishikawa, T.; Tokunaga, K.; Sugiu, K.; Liu, K.; Haruma, J.; Nishibori, M.; et al. Mannitol enhances therapeutic effects of intra-arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury. Neurosci. Lett. 2013, 554, 156–161. [Google Scholar] [CrossRef] [PubMed]
  68. Yu, S.; Tajiri, N.; Franzese, N.; Franzblau, M.; Bae, E.; Platt, S.; Kaneko, Y.; Borlongan, C.V. Stem cell-like dog placenta cells afford neuroprotection against ischemic stroke model via heat shock protein upregulation. PLoS ONE 2013, 8, e76329. [Google Scholar] [CrossRef]
  69. Dai, J.; Li, S.Q.; Qiu, Y.M.; Xiong, W.H.; Yin, Y.H.; Jia, F.; Jiang, J.Y. Migration of neural stem cells to ischemic brain regions in ischemic stroke in rats. Neurosci. Lett. 2013, 552, 124–128. [Google Scholar] [CrossRef]
  70. Yang, B.; Migliati, E.; Parsha, K.; Schaar, K.; Xi, X.; Aronowski, J.; Savitz, S.I. Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke 2013, 44, 3463–3472. [Google Scholar] [CrossRef]
  71. Ishizaka, S.; Horie, N.; Satoh, K.; Fukuda, Y.; Nishida, N.; Nagata, I. Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke. Stroke 2013, 44, 720–726. [Google Scholar] [CrossRef] [PubMed]
  72. Lu, S.S.; Liu, S.; Zu, Q.Q.; Xu, X.Q.; Yu, J.; Wang, J.W.; Zhang, Y.; Shi, H.B. In vivo MR imaging of intraarterially delivered magnetically labeled mesenchymal stem cells in a canine stroke model. PLoS ONE 2013, 8, e54963. [Google Scholar] [CrossRef] [PubMed]
  73. Byun, J.S.; Kwak, B.K.; Kim, J.K.; Jung, J.; Ha, B.C.; Park, S. Engraftment of human mesenchymal stem cells in a rat photothrombotic cerebral infarction model: Comparison of intra-arterial and intravenous infusion using MRI and histological analysis. J. Korean Neurosurg. Soc. 2013, 54, 467–476. [Google Scholar] [CrossRef]
  74. Rosenblum, S.; Wang, N.; Smith, T.N.; Pendharkar, A.V.; Chua, J.Y.; Birk, H.; Guzman, R. Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke 2012, 43, 1624–1631. [Google Scholar] [CrossRef]
  75. Lundberg, J.; Sodersten, E.; Sundstrom, E.; Le Blanc, K.; Andersson, T.; Hermanson, O.; Holmin, S. Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: Engraftment is dependent on cell type and adhesion molecule expression. Cell Transplant. 2012, 21, 333–343. [Google Scholar] [CrossRef]
  76. Vasconcelos-dos-Santos, A.; Rosado-de-Castro, P.H.; Lopes de Souza, S.A.; da Costa Silva, J.; Ramos, A.B.; Rodriguez de Freitas, G.; Barbosa da Fonseca, L.M.; Gutfilen, B.; Mendez-Otero, R. Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy? Stem Cell Res. 2012, 9, 1–8. [Google Scholar] [CrossRef]
  77. Mitkari, B.; Kerkela, E.; Nystedt, J.; Korhonen, M.; Mikkonen, V.; Huhtala, T.; Jolkkonen, J. Intra-arterial infusion of human bone marrow-derived mesenchymal stem cells results in transient localization in the brain after cerebral ischemia in rats. Exp. Neurol. 2013, 239, 158–162. [Google Scholar] [CrossRef]
  78. Andres, R.H.; Choi, R.; Pendharkar, A.V.; Gaeta, X.; Wang, N.; Nathan, J.K.; Chua, J.Y.; Lee, S.W.; Palmer, T.D.; Steinberg, G.K.; et al. The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain. Stroke 2011, 42, 2923–2931. [Google Scholar] [CrossRef]
  79. Gornicka-Pawlak, E.B.; Janowski, M.; Habich, A.; Jablonska, A.; Drela, K.; Kozlowska, H.; Lukomska, B.; Sypecka, J.; Domanska-Janik, K. Systemic treatment of focal brain injury in the rat by human umbilical cord blood cells being at different level of neural commitment. Acta Neurobiol. Exp. 2011, 71, 46–64. [Google Scholar] [CrossRef]
  80. Doucette, T.; Rao, G.; Yang, Y.; Gumin, J.; Shinojima, N.; Bekele, B.N.; Qiao, W.; Zhang, W.; Lang, F.F. Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model. Neoplasia 2011, 13, 716–725. [Google Scholar] [CrossRef] [PubMed]
  81. Chua, J.Y.; Pendharkar, A.V.; Wang, N.; Choi, R.; Andres, R.H.; Gaeta, X.; Zhang, J.; Moseley, M.E.; Guzman, R. Intra-arterial injection of neural stem cells using a microneedle technique does not cause microembolic strokes. J. Cereb. Blood Flow Metab. 2011, 31, 1263–1271. [Google Scholar] [CrossRef]
  82. Pendharkar, A.V.; Chua, J.Y.; Andres, R.H.; Wang, N.; Gaeta, X.; Wang, H.; De, A.; Choi, R.; Chen, S.; Rutt, B.K.; et al. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 2010, 41, 2064–2070. [Google Scholar] [CrossRef]
  83. Li, L.; Jiang, Q.; Ding, G.; Zhang, L.; Zhang, Z.G.; Li, Q.; Panda, S.; Lu, M.; Ewing, J.R.; Chopp, M. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. J. Cereb. Blood Flow Metab. 2010, 30, 653–662. [Google Scholar] [CrossRef]
  84. Lundberg, J.; Le Blanc, K.; Soderman, M.; Andersson, T.; Holmin, S. Endovascular transplantation of stem cells to the injured rat CNS. Neuroradiology 2009, 51, 661–667. [Google Scholar] [CrossRef]
  85. Bakondi, B.; Shimada, I.S.; Perry, A.; Munoz, J.R.; Ylostalo, J.; Howard, A.B.; Gregory, C.A.; Spees, J.L. CD133 identifies a human bone marrow stem/progenitor cell sub-population with a repertoire of secreted factors that protect against stroke. Mol. Ther. 2009, 17, 1938–1947. [Google Scholar] [CrossRef] [PubMed]
  86. Yong, R.L.; Shinojima, N.; Fueyo, J.; Gumin, J.; Vecil, G.G.; Marini, F.C.; Bogler, O.; Andreeff, M.; Lang, F.F. Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res. 2009, 69, 8932–8940. [Google Scholar] [CrossRef] [PubMed]
  87. Chung, D.J.; Choi, C.B.; Lee, S.H.; Kang, E.H.; Lee, J.H.; Hwang, S.H.; Han, H.; Lee, J.H.; Choe, B.Y.; Lee, S.Y.; et al. Intraarterially delivered human umbilical cord blood-derived mesenchymal stem cells in canine cerebral ischemia. J. Neurosci. Res. 2009, 87, 3554–3567. [Google Scholar] [CrossRef] [PubMed]
  88. Oyamada, N.; Itoh, H.; Sone, M.; Yamahara, K.; Miyashita, K.; Park, K.; Taura, D.; Inuzuka, M.; Sonoyama, T.; Tsujimoto, H.; et al. Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice. J. Transl. Med. 2008, 6, 54. [Google Scholar] [CrossRef]
  89. Guzman, R.; De Los Angeles, A.; Cheshier, S.; Choi, R.; Hoang, S.; Liauw, J.; Schaar, B.; Steinberg, G. Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke 2008, 39, 1300–1306. [Google Scholar] [CrossRef]
  90. Seyfried, D.M.; Han, Y.; Yang, D.; Ding, J.; Savant-Bhonsale, S.; Shukairy, M.S.; Chopp, M. Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage. Brain Res. 2008, 1224, 12–19. [Google Scholar] [CrossRef]
  91. Argibay, B.; Trekker, J.; Himmelreich, U.; Beiras, A.; Topete, A.; Taboada, P.; Perez-Mato, M.; Vieites-Prado, A.; Iglesias-Rey, R.; Rivas, J.; et al. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci. Rep. 2017, 7, 40758. [Google Scholar] [CrossRef]
  92. Lee, N.K.; Yang, J.; Chang, E.H.; Park, S.E.; Lee, J.; Choi, S.J.; Oh, W.; Chang, J.W.; Na, D.L. Intra-Arterially Delivered Mesenchymal Stem Cells Are Not Detected in the Brain Parenchyma in an Alzheimer’s Disease Mouse Model. PLoS ONE 2016, 11, e0155912. [Google Scholar] [CrossRef]
  93. Zhai, Q.Y.; Ren, Y.Q.; Ni, Q.S.; Song, Z.H.; Ge, K.L.; Guo, Y.L. Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1beta Ameliorate Cerebral Ischemic Reperfusion Injury in Rats. Biomolecules 2022, 12, 428. [Google Scholar] [CrossRef]
  94. Xin, H.; Wang, F.; Li, Y.; Lu, Q.E.; Cheung, W.L.; Zhang, Y.; Zhang, Z.G.; Chopp, M. Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Cells. Cell Transplant. 2017, 26, 243–257. [Google Scholar] [CrossRef]
  95. Seras-Franzoso, J.; Diaz-Riascos, Z.V.; Corchero, J.L.; Gonzalez, P.; Garcia-Aranda, N.; Mandana, M.; Riera, R.; Boullosa, A.; Mancilla, S.; Grayston, A.; et al. Extracellular vesicles from recombinant cell factories improve the activity and efficacy of enzymes defective in lysosomal storage disorders. J. Extracell. Vesicles 2021, 10, e12058. [Google Scholar] [CrossRef]
  96. Dabrowska, S.; Andrzejewska, A.; Strzemecki, D.; Muraca, M.; Janowski, M.; Lukomska, B. Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats. J. Neuroinflamm. 2019, 16, 216. [Google Scholar] [CrossRef]
  97. Shi, X.; Zhang, L.; Wu, S.; Zhang, C.; Mamtilahun, M.; Li, Y.; Zhang, Z.; Zuo, C.; Cui, F.; Li, W.; et al. A simple polydopamine-based platform for engineering extracellular vesicles with brain-targeting peptide and imaging probes to improve stroke outcome. J. Extracell. Vesicles 2025, 14, e70031. [Google Scholar] [CrossRef]
  98. Chung, S.J.; Lee, T.Y.; Lee, Y.H.; Baik, K.; Jung, J.H.; Yoo, H.S.; Shim, C.J.; Eom, H.; Hong, J.Y.; Kim, D.J.; et al. Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy. Stem Cells Int. 2021, 2021, 9886877. [Google Scholar] [CrossRef] [PubMed]
  99. Friedrich, M.A.; Martins, M.P.; Araujo, M.D.; Klamt, C.; Vedolin, L.; Garicochea, B.; Raupp, E.F.; Sartori El Ammar, J.; Machado, D.C.; Costa, J.C.; et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012, 21 (Suppl. 1), S13–S21. [Google Scholar] [CrossRef] [PubMed]
  100. Savitz, S.I.; Yavagal, D.; Rappard, G.; Likosky, W.; Rutledge, N.; Graffagnino, C.; Alderazi, Y.; Elder, J.A.; Chen, P.R.; Budzik, R.F., Jr.; et al. A Phase 2 Randomized, Sham-Controlled Trial of Internal Carotid Artery Infusion of Autologous Bone Marrow-Derived ALD-401 Cells in Patients With Recent Stable Ischemic Stroke (RECOVER-Stroke). Circulation 2019, 139, 192–205. [Google Scholar] [CrossRef] [PubMed]
  101. Moniche, F.; Gonzalez, A.; Gonzalez-Marcos, J.R.; Carmona, M.; Pinero, P.; Espigado, I.; Garcia-Solis, D.; Cayuela, A.; Montaner, J.; Boada, C.; et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: A pilot clinical trial. Stroke 2012, 43, 2242–2244. [Google Scholar] [CrossRef] [PubMed]
  102. Battistella, V.; de Freitas, G.R.; da Fonseca, L.M.; Mercante, D.; Gutfilen, B.; Goldenberg, R.C.; Dias, J.V.; Kasai-Brunswick, T.H.; Wajnberg, E.; Rosado-de-Castro, P.H.; et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen. Med. 2011, 6, 45–52. [Google Scholar] [CrossRef]
  103. Lee, P.H.; Lee, J.E.; Kim, H.S.; Song, S.K.; Lee, H.S.; Nam, H.S.; Cheong, J.W.; Jeong, Y.; Park, H.J.; Kim, D.J.; et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann. Neurol. 2012, 72, 32–40. [Google Scholar] [CrossRef]
  104. Banerjee, S.; Bentley, P.; Hamady, M.; Marley, S.; Davis, J.; Shlebak, A.; Nicholls, J.; Williamson, D.A.; Jensen, S.L.; Gordon, M.; et al. Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke. Stem Cells Transl. Med. 2014, 3, 1322–1330. [Google Scholar] [CrossRef] [PubMed]
  105. DaCosta, J.C.; Portuguez, M.W.; Marinowic, D.R.; Schilling, L.P.; Torres, C.M.; DaCosta, D.I.; Carrion, M.J.M.; Raupp, E.F.; Machado, D.C.; Soder, R.B.; et al. Safety and seizure control in patients with mesial temporal lobe epilepsy treated with regional superselective intra-arterial injection of autologous bone marrow mononuclear cells. J. Tissue Eng. Regen. Med. 2018, 12, e648–e656. [Google Scholar] [CrossRef]
  106. Bhatia, V.; Gupta, V.; Khurana, D.; Sharma, R.R.; Khandelwal, N. Randomized Assessment of the Safety and Efficacy of Intra-Arterial Infusion of Autologous Stem Cells in Subacute Ischemic Stroke. AJNR Am. J. Neuroradiol. 2018, 39, 899–904. [Google Scholar] [CrossRef] [PubMed]
  107. Giordano, R.; Canesi, M.; Isalberti, M.; Marfia, G.; Campanella, R.; Vincenti, D.; Cereda, V.; Ranghetti, A.; Palmisano, C.; Isaias, I.U.; et al. Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy. Front. Neurosci. 2021, 15, 723227. [Google Scholar] [CrossRef]
  108. Moniche, F.; Cabezas-Rodriguez, J.A.; Valverde, R.; Escudero-Martinez, I.; Lebrato-Hernandez, L.; Pardo-Galiana, B.; Ainz, L.; Medina-Rodriguez, M.; de la Torre, J.; Escamilla-Gomez, V.; et al. Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): A phase 2, randomised, open-label, standard-of-care controlled, multicentre trial. Lancet Neurol. 2023, 22, 137–146. [Google Scholar] [CrossRef]
  109. Hammadi, A.M.A.; Alhimyari, F. Intra-Arterial Injection of Autologous Bone Marrow-Derived Mononuclear Cells in Ischemic Stroke Patients. Exp. Clin. Transplant. 2019, 17 (Suppl. 1), 239–241. [Google Scholar] [CrossRef]
  110. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024, 23, 973–1003. [Google Scholar] [CrossRef]
  111. Henninger, N.; Fisher, M. Extending the Time Window for Endovascular and Pharmacological Reperfusion. Transl. Stroke Res. 2016, 7, 284–293. [Google Scholar] [CrossRef]
  112. Khatri, R.; McKinney, A.M.; Swenson, B.; Janardhan, V. Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology 2012, 79 (Suppl. 1), S52–S57. [Google Scholar] [CrossRef]
  113. Warach, S.; Latour, L.L. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 2004, 35 (Suppl. 1), 2659–2661. [Google Scholar] [CrossRef]
  114. Kawabori, M.; Weintraub, A.H.; Imai, H.; Zinkevych, L.; McAllister, P.; Steinberg, G.K.; Frishberg, B.M.; Yasuhara, T.; Chen, J.W.; Cramer, S.C.; et al. Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial. Neurology 2021, 96, e1202–e1214. [Google Scholar] [CrossRef]
  115. Kawabori, M.; Karasawa, Y.; Suenaga, J.; Nakamura, H.; Imai, H.; Yasuhara, T.; Tani, N.; Sasaki, T.; Kawasaki, T.; Totsuka, K.; et al. Relationship Between Location of Cell Transplantation and Recovery for Intracerebral Stem Cell Transplantation for Chronic Traumatic Brain Injury: Post-hoc Analysis of STEMTRA Trial. Neurotrauma Rep. 2025, 6, 106–114. [Google Scholar] [CrossRef]
  116. Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009, 10, 459–466. [Google Scholar] [CrossRef]
  117. Hamad, A.; Yusubalieva, G.M.; Baklaushev, V.P.; Chumakov, P.M.; Lipatova, A.V. Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies. Viruses 2023, 15, 547. [Google Scholar] [CrossRef] [PubMed]
  118. Shimizu, Y.; Gumin, J.; Gao, F.; Hossain, A.; Shpall, E.J.; Kondo, A.; Parker Kerrigan, B.C.; Yang, J.; Ledbetter, D.; Fueyo, J.; et al. Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma. J. Neurosurg. 2022, 136, 757–767. [Google Scholar] [CrossRef]
  119. Wakamoto, S.; Furukawa, T.; Kawabori, M.; Akino, M.; Kato, S.; Fuse, H.; Ohtsuki, S.; Torimoto, Y.; Fujimura, M.; Kino, S. Human platelet lysate produced from leukoreduction filter contents enables sufficient MSC growth. Stem Cell Res. Ther. 2025, 16, 205. [Google Scholar] [CrossRef] [PubMed]
  120. Borlongan, C.V.; Lee, J.Y.; D’Egidio, F.; de Kalbermatten, M.; Garitaonandia, I.; Guzman, R. Nose-to-brain delivery of stem cells in stroke: The role of extracellular vesicles. Stem Cells Transl. Med. 2024, 13, 1043–1052. [Google Scholar] [CrossRef] [PubMed]
Ijms 26 07405 g001
Figure 1. Cell sources used in animal experiment for intra-arterial transplantation.
Figure 1. Cell sources used in animal experiment for intra-arterial transplantation.
Ijms 26 07405 g001
Ijms 26 07405 g002
Figure 2. Cell doses used in animal experiments. Note that the Y-axis is on a logarithmic scale.
Figure 2. Cell doses used in animal experiments. Note that the Y-axis is on a logarithmic scale.
Ijms 26 07405 g002
Ijms 26 07405 g003
Figure 3. Transplantation timing of stem cell in the ischemic stroke model.
Figure 3. Transplantation timing of stem cell in the ischemic stroke model.
Ijms 26 07405 g003
Table 1. Cell modification.
Table 1. Cell modification.
MethodsModification DetailObjective
PretreatmentIL-1aAnti-inflammatory effect
neuregulin1Neural differentiation
MAPK inhibitorCell survival
BDNFNeural differentiation
Gene inductionNeural cell differentiationNeural differentiation
Integrin alpha 4Cell adhesion
The integrin Very Late Antigen-4 (VLA-4)Cell adhesion
NeurogeninNeural differentiation
CCL2Cell migration to damaged area
Cell purificationCD34Neurogenesis, angiogenesis
CD133Growth factor release
BDNF; brain-derived neurotrophic factor, CCL; C-C chemokine ligand, IL; interleukin, MAPK; mitogen-activated protein kinase.
Table 2. Mode of action.
Table 2. Mode of action.
Mode of ActionDetail of ActionEvaluated Factors
RegenerationNeurogenesisDCX, NeuN, MAP2, NGF, Nestin, SOX10, B-III tubulin, GFAP, Musashi1, Ki-67, Bur-U, Nogo-A, SYN, NF-200, NSE, Netrin-1, DCC
SynaptogenesisPSD95, Synaptophysin, GAP-43
AngiogenesisVEGF, HIF1a, Angiogenin, vWF, RECA, CD31
Damage reductionAnti-inflammatory effectIL-1b, IL-6, TNF-a, NLRP, IL-10, ED-1, MCP-1, Iba-1, CD45, IL-12, CD68, iNOS
Anti-oxidative stressGSH, MDA, Nitrite, catalase, Mitochondrial damage, ASIC1a, TBARS,
Anti-apoptosiscaspase 3, caspase 12, TUNEL, FluoroJade C, bFGF, SDF-1a, Bcl-2
Anti-ferroptosisDMT1, TFR1, p53, SLC7A11, GPX4
Neuro-protective functionSIRT-1, BDNF, NF-kb, neurotrophin-3, GDNF, HSP-27
Endoplasmic reticulum-protectiveGRP87, TrkB, p-eIF2α, ATF4, CHOP
BBB-protective functionAQP4, PKC-d, MMP-9, VEGF
Exosome releaseCD63
ASIC1a; acid sensing ion channel 1a, AQP; aquaporin, BBB; blood–brain barrier, Bcl-2; B-cell/CLL lymphoma 2, BDNF; brain-derived neurotrophic factor, bFGF; beta-fibrous growth factor, CHOP; CCATenhancer-binding protein homologous protein, DCC; deleted in colorectal cancer, DCX; double cortin, DMT1; divalent metal transporter 1, GAP; growth associated protein, GDNF; glial cell-derived neurotrophic factor, GFAP; glial fibrillary acidic protein, GSH; reduced glutathione, HIF1; Hypoxia-Inducible Factor 1, HSP; heat shock protein, Iba-1; Ionized calcium-binding adapter molecule 1, IL; interleukin, iNOS; inducible nitric oxide, MAP2; microtubule-associated protein 2, MCP-1; Monocyte Chemoattractant Protein-1, MDA; malondialdehyde, MMP; matrix metalloprotease, NeuN; neuronal nuclear protein, NF-kb; nuclear factor-kappa B, NF-200; neurofilament-200, NGF; nerve growth factor, NLRP; Nucleotide-binding oligomerization domain, Nogo-A; neurite growth inhibition marker, NSE; neuron-specific enolase, PKC; protein kinase C, PSD95; postsynaptic density protein 95, SDF; soluble-derived factor, SIRT; Sirtuin, SYN; neurite growth marker, TBARS; thiobarbituric acid reactive substances, TFR1; transferrin receptor 1, TNF; tissue necrosing factor, TUNEL; terminal deoxynucleotidyl transferase dUTP nick end labeling, VEGF; vascular endothelial growth factor, vWF; von Willebrand factor.
Table 3. Stem cell IA clinical trial.
Table 3. Stem cell IA clinical trial.
AuthorPMIDYearPhaseDiseaseNumber of ParticipantsTransplantation RouteCell SourceMain Inclusion CriteriaTransplantation TimingEndpoint TimingIA Cell Doses, (×105/kg *)Cell TrackingMain Conclusion
PatientsControl Total Cell NumbersCell Dose (×105/kg)
Battistella et al. [102] 211752862011Iischemic stroke6-IAAutologous BMMNCNIHSS; 4–172–3 months6 months1–5 × 10816–83 × 105/kg99m-TcFeasible and safe, cells soon distributed in the liver
Friedrich et al. [99]225076762012I/IIischemic stroke20-IAAutologous BMMNCNIHSS > 83–7 days6 months5–60 × 1078–100 × 105/kg-Feasible and safe, satisfactory clinical improvement occurred in 30% of patients
Moniche et al. [101]227642112012I/IIischemic stroke1010IAAutologous BMMNCNIHSS 15.6 (mean)5–9 days6 months1.6 × 108 (mean)26 × 105/kg-Safe, but no difference regarding the functional recovery was seen compared with control group
Lee et al. [103] 228292672012IImultiple-system atrophy1116IA and IVAutologous BMSCUMSRS 30–50-12 months4 × 1077 × 105/kg-Functional recovery and MRI findings were significantly better in treatment group
Banerjee et al. [104]251075832014Iischemic stroke5-IAAutologous BMMNC (CD34+)NIHSS > 87 days6 months1.2–2.7 × 1062–5 × 105/kg-Feasible and safe
DaCosta et al. [105] 276881592018I/IItemporal lobe epilepsy20-IAAutologous BMMNCMedically refractory epilepsy-6 months1–10 × 10816–160 × 105/kg-Feasible and safe, 40% of the patients became seizure-free after transplantation
Bhatia et al. [106] 295452532018IIischemic stroke1010IAAutologous BMMNCNIHSS > 78–15 days6 months5 × 10883 × 105/kg-Feasible and safe, better trend of recovery for treatment group (p = 0.07)
Savitz et al. [100]305867462019IIischemic stroke2917IAAutologous BMMNC (ALDH+)mRS > 39–15 days3 months1.6–7.5 × 1073–13 × 105/kg-No statistical differences were seen between treatment and control groups
Hammadi et al. [109]307775652019Iischemic stroke370IAAutologous BMMNCMCA territory3 months–5 years6 months5.0–6.0 × 10883–100 × 105/kg-67% of patients showed functional recovery
Chung et al. [98]347123352021Imultiple-system atrophy90IAAutologous BMSCUMSRS 30–50, Disease duration < 5 years-3 months-3, 6, 9 × 105/kg-Feasible and safe, medium and high dose groups showed a slower increase in UMSARS score than low group
Giordano et al. [107]347121132021Iprogressive supranuclear palsy70IAAutologous BMSCPSP diagnosis criteria-12 months77–156 × 10610–20 × 105/kg-Asymptomatic abnormal signs were found in the MRI, no significant functional recovery
Moniche et al. [108]366814462023IIischemic stroke3736IAAutologous BMMNCNIHSS 6–201–7 days6 months-0, 20, 50 × 105/kg-No statistical differences were seen between treatment and control groups
ALDH; aldehyde dehydrogenase, BMMNC; bone marrow mononuclear cell, BMSC; bone marrow-derived stem cell, IA; intra-arterial, IV; intravenous, NIHSS; National Institute of Health stroke scale, UMSARS; Unified multiple system atrophy rating scale. * body weight not indicated are calculated as 60 kg.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Honda, T.; Kawabori, M.; Fujimura, M. Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease. Int. J. Mol. Sci. 2025, 26, 7405. https://doi.org/10.3390/ijms26157405

AMA Style

Honda T, Kawabori M, Fujimura M. Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease. International Journal of Molecular Sciences. 2025; 26(15):7405. https://doi.org/10.3390/ijms26157405

Chicago/Turabian Style

Honda, Taishi, Masahito Kawabori, and Miki Fujimura. 2025. "Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease" International Journal of Molecular Sciences 26, no. 15: 7405. https://doi.org/10.3390/ijms26157405

APA Style

Honda, T., Kawabori, M., & Fujimura, M. (2025). Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease. International Journal of Molecular Sciences, 26(15), 7405. https://doi.org/10.3390/ijms26157405

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop