Next Article in Journal
Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo
Next Article in Special Issue
Self-Organized Liver Microtissue on a Bio-Functional Surface: The Role of Human Adipose-Derived Stromal Cells in Hepatic Function
Previous Article in Journal
The Mitochondrial Pentatricopeptide Repeat Protein PPR18 Is Required for the cis-Splicing of nad4 Intron 1 and Essential to Seed Development in Maize
Previous Article in Special Issue
Syndecan-1 Facilitates the Human Mesenchymal Stem Cell Osteo-Adipogenic Balance
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI

Rami Ahmad Shahror
Chung-Che Wu
Yung-Hsiao Chiang
2,3,4,5,6,* and
Kai-Yun Chen
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland, School of Medicine, Baltimore, MD 21201, USA
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 110, Taiwan
TMU Neuroscience Research Center, Taipei Medical University, Taipei 110, Taiwan
Department of Neurosurgery, Taipei Medical University Hospital, Taipei 110, Taiwan
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 4051;
Submission received: 19 May 2020 / Revised: 29 May 2020 / Accepted: 4 June 2020 / Published: 5 June 2020
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine 2.0)


Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs’ biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.

Graphical Abstract

1. Introduction

Traumatic brain injury (TBI) is the most common form of head injury and is estimated to result in death or hospital admission for more than 10 million people annually worldwide [1,2]. The leading causes of TBI are transportation-related incidents, falls, and violence [3,4]. Although the incidence of TBI is independent of age and gender, the highest TBI incidence was in males aged 20–30 years [4]. The direct and indirect expenses of TBI in the United States in 2000 alone were estimated to be over $76 billion, highlighting the financial burden of TBI for health care systems and individuals [5]. Monotarget therapy for TBI was not effective due to the multifactorial and heterogeneous nature of TBI since various manifestations occur in different parts and timepoints post-injury [6]. Therefore, an ideal therapeutic strategy would have a multitarget, simultaneous action to induce a robust treatment for TBI [6]. One promising therapeutic option that has multitarget, simultaneous action is mesenchymal stem cell (MSC)-based therapy due to their secretion of neurotrophic factor and other neuroprotective factors [7].
MSCs have gained significant attention as an emerging therapeutic intervention for various CNS diseases and injuries such as spinal cord injury, multiple sclerosis, ischemic stroke, as well as TBI [8,9,10,11,12,13,14,15,16]. MSCs are considered promising therapeutic cells for clinical utility, owing to their ease of isolation, immunosuppression features that allow allogeneic transplantation without immunosuppression, and lack of ethical controversies [17]. However, the therapeutic potency of MSCs in vivo is affected by their poor survival, homing, and the functionality of the cells at the injured tissue. Advances in MSCs’ biology, molecular biology, and genetic engineering have opened up new approaches to improve MSC-based therapy potency. Genetic modification of MSCs to enhance their survival, homing, and sustainable release of therapeutic factors is particularly attractive.
In this review, we will highlight the pathology of TBI and the recent application of MSCs for TBI treatment. We will also discuss the approaches for the genetic modification of MSCs. The latest application of genetically modified MSCs for TBI treatment will also be addressed.

2. Search Strategy and Selection Criteria

The databases used to select the most relevant papers included in this article were: Google Scholar, Web of Science, MEDLINE, and PubMed. Keywords for searching (selection criteria): mesenchymal stem cells, traumatic brain injury, cell therapy, genetic modification, neurogenesis. We set dates of searching: 1996–2019. We selected only the available English articles for performing this study.

3. Neuroinflammatory Cascade of TBI

TBI is a heterogeneous and complex brain injury that occurs due to the occurrence of external mechanical force. The external mechanical force can transfer to the head directly (collision, assault) or indirectly (sudden acceleration-deceleration of the head). TBI results in two main injuries, based on the cellular and histological pathology: (1) primary injury that occurs when an external mechanical force transferred to the head, and (2) secondary injury cascades that are activated by the primary injury. The primary injury of TBI occurs at the moment of insult and results in rapid necrotic cell death. However, the secondary injury of TBI is more destructive, characterized by a progressive apoptotic cell death that becomes evident within several hours to days after trauma and can extend for weeks to months after the initial injury [18].
Advances in the diagnosing of CNS’s pathological conditions and innovative pharmacological protocols helped to discover the molecular cascade and expand our understanding of the pathological basis of neurological diseases and brain injuries [19]. Extensive research has elucidated the associated molecular cascades that underpin the neuronal dysfunction and death evident in the secondary injury of TBI; these include glutamate excitotoxicity, ischemia, intracellular calcium dysregulation, oxidative stress, and neuroinflammation (see Figure 1) [20,21,22,23,24,25,26,27,28]. TBI can result in loss of other brain cells such as astrocytes, which can affect these cells’ functions and viability [29,30]. There is increasing recognition that TBI heightens the risk of several neurodegenerative diseases [31,32].
Inflammation is a hallmark of the secondary injury following TBI that contributes to neuronal damage and affects neural repair mechanisms. Inflammation is considered as the major cause of secondary cell death following TBI [33,34,35]. Following the initial injury, injured axons produce debris that triggers an excessive and continuous systemic inflammatory response that leads to immediate cell death [18,36,37,38]. The injured cells release both pro-inflammatory cytokines which activate the microglia, the main resident immune cells in the brain. Previously, one study demonstrated that activated microglial cells can be detected at eight weeks in chronic TBI and is associated with CA3 cell loss, and dysfunctional cell proliferation in the hippocampus [33]. The compromised BBB and cytokines release allows the infiltration and activation of peripheral immune cells such as leukocytes, and macrophages that can transform into microglia that add a further immune response to TBI [39,40,41,42,43]. Although the microglia can eliminate cell debris and promote tissue remodeling, the increased inflammatory responses can lead to increased white matter injury and cell death due to the excessive secretion of pro-inflammatory cytokines that trigger the secondary injury cascade that can last for years post-injury [44,45,46,47,48,49,50,51,52,53]. Ramlackhansingh and colleagues showed that chronic inflammation following the initial impact of TBI might persist for up to 17 years post-TBI [54]. These observations was confirmed in humans by postmortem histological evidence that showed that microglial activation could be present after many years following TBI [47].

4. MSC-Based Therapy for TBI

4.1. MSCs’ Biology

MSCs are multipotent stromal cells that can differentiate into a few unique mesenchymal cell types. The International Society for Cellular Therapy proposed the following criteria to define human MSCs: (1) plastic adherent in vitro; (2) positive for the surface markers CD105, CD73, and CD90 and negative for CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR; and (3) capable of differentiating into osteoblasts, adipocytes, and chondroblasts in vitro under standard differentiating conditions [55].
MSCs are most often isolated from bone marrow by a density gradient centrifugation method. Other sources of MSCs are umbilical cord blood (UCB), adipose tissue or placenta, and dental pulp. However, MSCs have heterogenic phenotypes due to the different source tissue microenvironments, and this may confer distinct functional properties on the cells [56]. For instance, adipose tissue-derived MSCs displayed a pronounced expression of the surface markers CD34+, PODXL, CD36, CD49f, CD106 and CD146, and more adipogenic differentiation capability compared to bone marrow-derived MSCs [57]. Another study examined the immunoregulatory properties of placenta-derived MSCs and other cells derived from the same source and showed that placenta-derived MSCs were more immunosuppressive [58]. Differences in cell donors might affect cells’ characterization. For example, one study showed that the expression of interleukin-1α in MSCs isolated from young rats was eight-fold higher than in cells from aged rats [59].
MSCs are known to have paracrine and autocrine activities for injured tissues in the brain due to their multifunctional secretome [60]. Few studies have demonstrated that MSCS were able to differentiate into neuronal cells following transplantation in brain tissue [61,62,63]. However, the neurological benefits observed in these studies attributed to MSCs’ paracrine and cytokine actions rather their differentiation into neuronal cells due to low engraftment of MSCs into brain tissue [63,64]. Thus, maintaining MSCs’ stemness for prolonged period post-transplantation that allows the cells to release paracrine effectors and trophic factors for more extended periods is essential to improve the functional outcome in the injured brain. Although there is no clinical trial has reported the development of cancer from experimentally given MSCs, potential tumorigenicity, promoting tumor growth and metastasis have reported in in vitro and preclinical model [65,66,67]. However, its essential to consider the the immunological status of experimental animals in studies designed for evaluation of tumorigenicity of MSC as many studies use immune-deficient animal models.
The mechanism of action of MSCs depends on their homing ability toward the injured tissues and the secretion of trophic factors that facilitate the endogenous repair processes. The most well-known secreted factors by MSCs are the brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), glial cell-line derived neurotrophic factor (GDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) [68]. The factors released by MSCs were found to mitigate local inflammation, reduce free radical levels, inhibit apoptosis, and promote the angiogenesis, proliferation, and differentiation of the injured tissue’s stem cells [69].

4.2. MSCs’ Application for TBI Treatment

MSCs are emerging as a potential stem cell-based therapy for TBI (see Figure 2) [62,70,71,72,73,74]. Direct transplantation of MSCs into the injured brain tissue during cranial repair operations in TBI patients has shown no adverse effects, indicating the safe profile of MSCs in clinical application for the treatment of TBI [75]. Direct delivery of MSCs to injured tissue in the brain, or indirect delivery through intravenous or intra-arterial injections, can cause significant amelioration of TBI-induced motor and cognitive deficits in preclinical models. Accumulated preclinical studies demonstrated that systemically infused MSCs were able to bypass the blood-brain barrier and elevate the expression of neuroprotective factors in the brain after TBI [70]. Besides, MSC transplantation following TBI has shown that these cells can migrate and survive in the injury site, where they contribute to neuroprotection, neural repair, and motor function [72,76]. Furthermore, MSCs’ secretome can modulate the inflammatory response following TBI by decreasing cytokines’ expression in the brain tissue [77].
MSCs can reduce neuroinflammation and improve functional recovery after TBI [78]. Intravenous MSC transplantation two hours after TBI in a weight-drop rat TBI model reduced the peripheral infiltration of neutrophils (MPO+) and CD3+ lymphocytes, activation/infiltration of macrophages/microglia, as well as pro-inflammatory cytokines [78]. These anti-inflammatory effects of MSCs were associated with reduced apoptosis in the injured tissues and early functional improvement. MSC transplantation found to improve functional outcomes in TBI via inhibiting the microglial polarization toward the M1 pro-inflammatory microglial phenotype [79]. MSCs-based therapy was able to augment the excessive acute pro-inflammatory response to the level needed for debris clearance. Such regulation of the pro-inflammatory response can prevent the development of chronic neuroinflammation and promote neuroprotection in TBI. The anti-inflammatory effects of MSCs are potential targets for further enhancement of MSCs’ therapeutic effects in TBI by reducing secondary injury, which ultimately leads to functional improvement.
Decreased hippocampal neurogenesis following TBI at the acute phase is well-established, demonstrated by a robust reduction in immature neurons in the hippocampus [80,81,82]. A recent study reported that TBI impaired hippocampal neurogenesis at the chronic phase, evidenced by a significant decrease in immature neurons in the hippocampus, which correlated with hippocampal-dependent learning and memory deficits [83]. Several studies showed that TBI also impaired hippocampal neurogenesis in terms of dendrite development arborization, morphology, and functional integration into the hippocampal neuronal network [83,84]. Several studies have demonstrated that TBI can lead to axonal sprouting in hippocampal mossy fiber pathways that have been linked with abnormal excitation and post-traumatic seizures [85,86,87,88,89]. In human, TBI insult can cause abnormal axonal growth that leads to aberrant hippocampal mossy fiber sprouting [90].
Furthermore, the impairments in dendrite development, arborization, and morphology of immature neurons in the hippocampus ultimately lead to post-traumatic impairment in learning and memory by affecting the functional synaptic integration and disrupting signaling transduction, which is essential for action potential propagation in neurons [91]. MSCs can promote and enhance the endogenous regeneration of the injured tissue. For instance, Munoz and colleagues showed that MSCs facilitate the proliferation, migration, and differentiation of endogenous neural stem cells (NSCs) following direct engraftment of MSCs in the hippocampus [92]. Several studies demonstrated that showed that MSC transplantation following TBI rescued the impairment in the dendrite length of the newborn neuron in the injured hippocampus [83]. Besides, the secretome from MSCs promoted the survival and proliferation of endogenous neural stem cells in the injured brains of mice with TBI [62].
Intravenous MSC delivery for TBI therapy has been increasingly used in preclinical studies. Although the majority of these studies suggest that significant numbers of administered MSC are initially trapped in the lungs, MSC reaching the damaged brain after crossing the BBB improved neurobehavioral scores were still reported [70,93,94]. Several MSCs tracking studies showed that intravenously administered MSC tend to migrate from the lungs to other tissues such as the spleen and liver, or sites of injury in short periods [95,96,97,98,99]. Several studies have indicated that MSCs might cross the BBB via molecular mechanisms that involve adhesion molecules, chemokines, and proteases using in vitro BBB models [100,101,102,103,104]. For example, Steingen et al. showed that MSCs could integrate into the endothelium via the adhesion molecules VCAM-1/VLA-4 and β1 integrin then cross the endothelial of BBB into host tissue through the use of plasmic podia [100]. In TBI, MSC administration increased the production of Tissue Inhibitor of Matrix Metalloproteinase 3 (TIMP3) that attenuate the increased BBB’s permeability after injury in an animal model [105]. Although These studies suggest that MSCs can cross the BBB to the site of injury or inflammation, the compromised the integrity BBB flowing TBI insult might result in a passive accumulation MSC in the brain via entrapment [106].

5. Genetically Modified MSC-Based Therapy for TBI

As pointed out in the previous section, MSC-based therapy for TBI is a promising option to facilitate recovery of the injured tissue in the brain. However, due to the harsh microenvironment of the injured tissue and the complexity of TBI injury, the development of new strategies to improve the homing and survival and paracrine properties of MSCs at the injury site is urgently needed. Genetic modification is a promising strategy to maximize MSCs’ therapeutic capacity in vivo. Genetic modification of MSCs is usually achieved using viral vectors, although the use of non-viral vectors is on the rise.

5.1. Viral Vector-Mediated Genetic Modification

Viral vectors are the most common and efficient vectors for the genetic modification of host cells due to their natural ability to infect the cells, bypass the cellular barriers and deliver genetic material into the host cell’s nucleus. Integrative viral vectors, such as retrovirus and lentivirus, are very efficient vectors for the genetic modification of host cells as they can deliver and integrate the gene of interest into the host cell’s genome. While retrovirus can only transduce dividing cells with a smaller loading capacity (8 kb), lentivirus can transduce dividing and non-dividing cells with larger loading (9 kb) [107,108]. Although integrative vectors are very efficient in genetic modification, they raise safety concerns due to the possibilities of insertional mutagenesis induction and proto-oncogene activation in the host cells [109]. Non-integrative viral vectors are vectors that can infect the host cells without integration with the host genome. Adeno-associated virus (AAV) is the most common non-integrative viral vector used for genetic modification due to its non-pathogenic features, strong expression of the gene of interest, and low risk of insertional mutagenesis. Although viral vector-mediated genetic modification may be appealing for MSC-based therapy, the long-term safety of viral gene therapy remains a concern. Furthermore, the transduced cells might present viral antigens that could potentially activate an immune response in vivo following transplantation [110]. A benefit-to-risk ratio should be considered before such cell therapy be practical.

5.2. Non-Viral Vector-Mediated Genetic Modification

Advancements in molecular biology and genetic engineering have led to the synthesis and design of non-viral vectors that can deliver large genetic materials into the cells. Other advantages of non-viral vectors are the possibility to control the expression of the gene of interest via regulatory manipulation, their reduced immunotoxicity, and is easier and cheaper to produce on a large scale compared to viral vectors. Preconditioning can improve the intrinsic therapeutic properties of MSCs against the harsh microenvironment within its transplanted milieu, which is predominant in TBI injured tissue. Several studies have reported that preconditioning can enhance the interaction between MSCs and the innate/adaptive immune responses. Chen et al. demonstrated that culturing MSCs under hypoxic conditions improves the cells’ expression of more antiapoptotic proteins, IL-8 and IL-6 [111]. Similar results were reported by Jiang et al. that showed hypoxic conditions improved IL-10 and FasL in vitro in MSCs [112]. The enhanced immunomodulation, in turn, mitigate the inflammation and encourage the injured tissue repair and regeneration.
Non-viral integrative vectors such as excisable systems and transposons often disrupt the host genome, leading to limited applications for these vectors in the genetic modification of therapeutic cells. Non-integrative vectors such as episomal vectors are less toxic compared to integrative viral vectors [113]. Although the non-viral vector-based methods for genetic modification offer an exciting promise, their use in the genetic modification of therapeutic cells might be hampered by transient expression of the gene of interest and vector damage following cell infection [114]. Although non-viral genetic modification methods have low transfection efficiency compared to viral-based methods, its ability to alleviate the safety concerns with reduced immunogenicity makes it more likely to enter the clinical trials.

5.3. Application of Genetically Modified MSCs for TBI Treatment

Genetic modification of MSCs involves inducing the overexpression of factors that are critical for MSCs’ therapeutic effects [115]. Such factors can be proteins that enhance the homing and survival of MSCs and the secretion of trophic factors that facilitate the restorative processes at the injury site. Overexpression of factors that have anti-inflammatory and neuroprotective effects is a particularly promising modification for TBI therapy. Genetic modification of MSCs will have more advantages compared to classical gene therapy strategies, which are based on direct infection of the targeted tissue in vivo by lentiviral or AAV vectors. In contrast, MSCs are considered a safer approach for gene therapy. Also, the viral transfection of MSCs can be easily controlled ex vivo and limited to one to two viral vectors per MSC genome to follow the FDA regulation for stem cells and gene-based therapy trials. Importantly, genetic modification can custom MSCs for the treatment of a wide range of brain injuries such as stroke and TBI.
There is growing evidence supporting the efficiency of using genetically modified MSC-based therapy for TBI in preclinical models (Figure 3). One promising approach for using genetically modified MSCs for TBI treatment is to overexpress factors that have anti-inflammatory effects, as inflammation is one of the most well-established mechanisms of the secondary injury of TBI. The application of genetically modified MSCs to overexpress an anti-inflammatory cytokine, in particular, IL-10, to reduce inflammation has been evaluated in preclinical models of various injuries and disorders, including arthritis, autoimmune encephalomyelitis, ischemia-reperfusion injury in the lung, graft-versus-host disease, and ischemic stroke [116,117,118,119,120]. A recent study showed that using genetically modified MSCs to overexpress IL-10 mitigated TBI deficits by reducing inflammation, preventing apoptosis and tissue loss, and reducing the production of TNF-αin a rat model of TBI [121]. The increase of IL-10 in accordance with the decrease in TNF-α promotes a shift in the macrophages/microglia activation state, from classical to alternative CD163-activated cells.
Another promising strategy for enhancing the therapeutic potential of MSCs by genetic modification is by enhancing their homing abilities to the injured tissue. MSCs can migrate to sites of TBI injury [72,76]. A recent study showed that transplanted MSCs can be detected at the injury site as early as 24 h later and can survive for 28 days post-injury in a mouse model of TBI [83,122]. Recent studies have shown that genetic modification of MSCs is a feasible approach to improve MSCs’ homing abilities in TBI. For instance, MSCs expressing CXCR4 are highly attracted to the potent chemoattractant stromal cell-derived factor-1 (SDF-1), which was found to be dramatically overexpressed at the zone of lesions by astrocytes and endothelial cells. The SDF-1/CXCR4 axis promotes MSCs homing to injury sites in the brain and other organs.Wang and colleagues showed that genetically modified MSCs that overexpress CXC chemokine receptor 4 (CXCR4) enhanced homing abilities to the injury site in a TBI model Due to the improved homing of these cells, paracrine secretion of cytokines and growth factors was improved, leading to enhanced vasculogenesis and neuroprotection, improved blood supply, recovery of axon connectivity, and behavioral ability in treated mice. Another promising target to improve MSCs homing is fibroblast growth factor 21 (FGF21), a metabolic regulator that exhibits neuroprotective effects and promotes cells’ migration in vitro. Previous studies have shown that FGF21 improves cell migration in various cells type in vitro, including fibroblasts and cardiomyocytes. For instance, treatment with FGF21 mimics compound was able to improve human umbilical vein endothelial cells (HUVECs) migration. This study showed that FGF21 treatment-induced migration via the activation of eNOS/PI3K/AKT pathways. Another study showed that FGF21 promotes cells’ migration via the β-catenin signaling cascade and c-Jun N-terminal kinase (JNK) signaling, an essential regulator of cell migration, in fibroblasts in vitro [123,124,125]. A recent study showed that FGF21 overexpression in MSCs by genetic engineering enhanced the MSCs migration in vitro and improved the homing abilities of MSCs to the injury site in a mouse model of TBI [122]. However, the exact mechanism by which FGF21 improved the homing of MSCs is still unclear.
Even if the implanted cells are successfully migrated to the site of injury in the brain, their neuroprotective function within the harsh microenvironment is found to be reduced. Overexpressing neuroprotective genes such as BDNF, glucagon-like peptide-1 (GLP-1), FGF21 has had the dual benefit of promoting the homing and survival of transplanted MSCs as well as the paracrine factor-induced recovery and neuroprotection of the host’s brain-injured area. In one study, MSCs isolated from the umbilical cord and genetically modified to overexpress BDNF increased their ability to migrate to and survive in cerebral tissues, and mitigated neurological deficits more efficiently than MSCs alone in rats with TBI [126]. Cerebral transplantation of encapsulated MSCs that overexpress glucagon-like peptide-1 (GLP-1), a neuroprotective substance against excitotoxicity in vitro and in vivo that exhibits antioxidant effects, were able to reduce the neuronal cell loss in the hippocampus and cortical neuronal and glial defects in TBI rat models [127]. These effects were less pronounced in animals treated with MSCs alone. Recently, a study showed that the transplantation of MSCs that overexpress FGF21 improved the cognitive functions at the chronic phase following TBI in a mouse model [83]. Although the treatment with MSCs alone also showed partial functional recovery, treatment with MSC-FGF21 exhibited more pronounced functional recovery. MSC-FGF21 treatment was associated with enhanced hippocampal neurogenesis, enhanced FGF21 protein levels, and reduced morphological deficits in immature neurons in the injured hippocampus.
Accumulated studies have identified promising therapeutic cellular targets for TBI, especially those who play a critical role in the pathogenesis of traumatic brain injury. In vitro and preclinical studies that explored these targets showed promising therapeutic results that able to ameliorates TBI-induced cellular and functional consequences. For example, exogenous neuroprotective factors like CuZn-SOD and other neurotrophins such as NGF, BDNF, and FGF-2 exhibited neuroprotective effects in vitro, and in vivo [128,129,130,131,132,133]. Their rapid deactivation, off-target effects on the PNS, and low permeability through the BBB would limit their application in clinical use for TBI [134]. However, that makes them excellent candidates for genetically modified MSC-based therapy that would improve MSCs’ potency and therapeutic potential. Other examples of potential candidates for MSC genetic modification are miRNAs such as miR-195, miR-24, and miR-19b due to their role in the neuronal apoptosis, regeneration, and neurodegenerative processes. Several reports showed significant alterations of miRNAs expression hippocampus and plasma following TBI [135,136]. MSCs offer an excellent delivery system for miRNAs through their exosomes that can bypass BBB, and maintain the stability and functionality of the miRNA due to their lipid bilayers. These targets and factors are promising future candidates to develop target-specific genetically modified MSC-based therapy and enhance MSCs’ potency to mitigate TBI consequences.
The risk profile of genetically modified MSCs-based therapy for TBI depends on many risk factors, which include the type of genetic modification, the target of the inserted gene, their differentiation potency, and proliferation capacity, the homing ability of MSCs, the long-term survival of engrafted cells, the route of administration. Currently, there is no clinical experience with genetically modified MSCs-based therapy for TBI. Based on MSCs’ of immunomodulation characteristics and viral vector-mediated genotoxicity, the risks associated with tumorigenesis are considered high. In contrast, the vast majority of small-sized clinical trials conducted with MSC in TBI, or direct injection of viral vector into the human brain has not reported significant health concerns [75,137,138,139,140,141,142,143]. These clinical evidences suggest that use genetically modified MSC, via viral or non-viral-based modification methods, could be relatively safe for clinical application.

6. Conclusions

Numerous studies have outlined the beneficial effects of genetically modified MSC-based therapy for TBI. Genetic modification of MSCs enhances their viability and proliferative, migratory, and functional properties, thus increasing their therapeutic potential. Importantly, genetic modification of MSCs offers a safe, targeted, and robust option for gene delivery in gene-based therapy. The findings, as mentioned earlier, reveal that genetically modified MSC-based therapy could lead to the translation of preclinical studies into effective and safe targeted therapies for TBI.

Author Contributions

Funding acquisition, Y.-H.C. and K.-Y.C.; Resources, Y.-H.C. and K.-Y.C.; Supervision, Y.-H.C. and K.-Y.C.; Writing—original draft, R.A.S.; Review & editing, C.-C.W., Y.-H.C. and K.-Y.C. All authors have read and agreed to the published version of the manuscript.


This work was supported by the Ministry of Science and Technology Grants, Taiwan (MOST 104-2923-B-038-004-MY2, MOST 107-2314-B-038-063, MOST 108-2321-B-038-008 and MOST 107-2314-B-038-042) and Taipei Medical University (TMU 105-AE1-B03, TMU 106-5400-004-400, TMU 106-5310-001-400, DP2-107-21121-01-N-05 and DP2-108-21121-01-N-05-01).

Conflicts of Interest

The authors declare no conflict of interest.


  1. Murray, C.J.; Lopez, A.D. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997, 349, 1269–1276. [Google Scholar] [CrossRef]
  2. Hyder, A.A.; Wunderlich, C.A.; Puvanachandra, P.; Gururaj, G.; Kobusingye, O.C. The impact of traumatic brain injuries: A global perspective. NeuroRehabilitation 2007, 22, 341–353. [Google Scholar] [CrossRef] [Green Version]
  3. Thurman, D.J.; Alverson, C.; Dunn, K.A.; Guerrero, J.; Sniezek, J.E. Traumatic brain injury in the United States: A public health perspective. J. Head Trauma Rehabil. 1999, 14, 602–615. [Google Scholar] [CrossRef] [PubMed]
  4. Langlois, J.A.; Rutland-Brown, W.; Wald, M.M. The epidemiology and impact of traumatic brain injury: A brief overview. J. Head Trauma Rehabil. 2006, 21, 375–378. [Google Scholar] [CrossRef] [Green Version]
  5. Coronado, V.G.; Xu, L.; Basavaraju, S.V.; McGuire, L.C.; Wald, M.M.; Faul, M.D.; Guzman, B.R.; Hemphill, J.D.; Centers for Disease Control and Prevention. Surveillance for traumatic brain injury-related deaths—United States, 1997–2007. MMWR Surveill. Summ. 2011, 60, 1–32. [Google Scholar] [PubMed]
  6. Somayaji, M.R.; Przekwas, A.J.; Gupta, R.K. Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms. Curr. Neuropharmacol. 2018, 16, 484–504. [Google Scholar] [CrossRef] [PubMed]
  7. Park, S.E.; Lee, N.K.; Na, D.L.; Chang, J.W.; Chang, J.W. Optimal mesenchymal stem cell delivery routes to enhance neurogenesis for the treatment of Alzheimer’s disease. Histol. Histopathol. 2018, 33, 533–541. [Google Scholar] [PubMed]
  8. Osaka, M.; Honmou, O.; Murakami, T.; Nonaka, T.; Houkin, K.; Hamada, H.; Kocsis, J.D. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res. 2010, 1343, 226–235. [Google Scholar] [CrossRef] [PubMed]
  9. Xu, P.; Yang, X. The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review. Cell Transpl. 2019, 28, 36–46. [Google Scholar] [CrossRef] [Green Version]
  10. Muniswami, D.M.; Kanthakumar, P.; Kanakasabapathy, I.; Tharion, G. Motor Recovery after Transplantation of Bone Marrow Mesenchymal Stem Cells in Rat Models of Spinal Cord Injury. Ann. Neurosci. 2019, 25, 126–140. [Google Scholar] [CrossRef]
  11. Qi, L.; Xue, X.; Sun, J.; Wu, Q.; Wang, H.; Guo, Y.; Sun, B. The Promising Effects of Transplanted Umbilical Cord Mesenchymal Stem Cells on the Treatment in Traumatic Brain Injury. J. Craniofac. Surg. 2018, 29, 1689–1692. [Google Scholar] [CrossRef]
  12. Anbari, F.; Khalili, M.A.; Bahrami, A.R.; Khoradmehr, A.; Sadeghian, F.; Fesahat, F.; Nabi, A. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury. Neural Regen. Res. 2014, 9, 919–923. [Google Scholar] [CrossRef]
  13. van Velthoven, C.T.; Sheldon, R.A.; Kavelaars, A.; Derugin, N.; Vexler, Z.S.; Willemen, H.L.; Maas, M.; Heijnen, C.J.; Ferriero, D.M. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke 2013, 44, 1426–1432. [Google Scholar] [CrossRef] [Green Version]
  14. Choi, Y.K.; Urnukhsaikhan, E.; Yoon, H.H.; Seo, Y.K.; Park, J.K. Effect of human mesenchymal stem cell transplantation on cerebral ischemic volume-controlled photothrombotic mouse model. Biotechnol. J. 2016, 11, 1397–1404. [Google Scholar] [CrossRef]
  15. Wang, F.; Tang, H.; Zhu, J.; Zhang, J.H. Transplanting Mesenchymal Stem Cells for Treatment of Ischemic Stroke. Cell Transpl. 2018, 27, 1825–1834. [Google Scholar] [CrossRef]
  16. Pires, A.O.; Teixeira, F.G.; Mendes-Pinheiro, B.; Serra, S.C.; Sousa, N.; Salgado, A.J. Old and new challenges in Parkinson’s disease therapeutics. Prog. Neurobiol. 2017, 156, 69–89. [Google Scholar] [CrossRef] [PubMed]
  17. 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] [PubMed]
  18. Werner, C.; Engelhard, K. Pathophysiology of traumatic brain injury. Br. J. Anaesth. 2007, 99, 4–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Ganau, L.; Prisco, L.; Ligarotti, G.K.I.; Ambu, R.; Ganau, M. Understanding the Pathological Basis of Neurological Diseases Through Diagnostic Platforms Based on Innovations in Biomedical Engineering: New Concepts and Theranostics Perspectives. Medecines (Basel) 2018, 5, 22. [Google Scholar] [CrossRef] [Green Version]
  20. Maas, A.I.; Stocchetti, N.; Bullock, R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008, 7, 728–741. [Google Scholar] [CrossRef]
  21. Bains, M.; Hall, E.D. Antioxidant therapies in traumatic brain and spinal cord injury. Biochim. Biophys. Acta 2012, 1822, 675–684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Das, M.; Mohapatra, S.; Mohapatra, S.S. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J. Neuroinflammation 2012, 9, 236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Chiu, C.C.; Liao, Y.E.; Yang, L.Y.; Wang, J.Y.; Tweedie, D.; Karnati, H.K.; Greig, N.H.; Wang, J.Y. Neuroinflammation in animal models of traumatic brain injury. J. Neurosci. Methods 2016, 272, 38–49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Witcher, K.G.; Bray, C.E.; Dziabis, J.E.; McKim, D.B.; Benner, B.N.; Rowe, R.K.; Kokiko-Cochran, O.N.; Popovich, P.G.; Lifshitz, J.; Eiferman, D.S.; et al. Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation. Glia 2018, 66, 2719–2736. [Google Scholar] [CrossRef]
  25. Greve, M.W.; Zink, B.J. Pathophysiology of traumatic brain injury. Mt. Sinai J. Med. 2009, 76, 97–104. [Google Scholar] [CrossRef]
  26. Barkhoudarian, G.; Hovda, D.A.; Giza, C.C. The molecular pathophysiology of concussive brain injury. Clin. Sports Med. 2011, 30, 33–48. [Google Scholar] [CrossRef]
  27. Morganti-Kossmann, M.C.; Rancan, M.; Stahel, P.F.; Kossmann, T. Inflammatory response in acute traumatic brain injury: A double-edged sword. Curr. Opin. Crit. Care 2002, 8, 101–105. [Google Scholar] [CrossRef]
  28. Schmidt, O.I.; Heyde, C.E.; Ertel, W.; Stahel, P.F. Closed head injury—An inflammatory disease? Brain Res. Brain Res. Rev. 2005, 48, 388–399. [Google Scholar] [CrossRef]
  29. Chen, Y.; Swanson, R.A. Astrocytes and brain injury. J. Cereb. Blood Flow Metab. 2003, 23, 137–149. [Google Scholar] [CrossRef]
  30. Barreto, G.E.; Gonzalez, J.; Torres, Y.; Morales, L. Astrocytic-neuronal crosstalk: Implications for neuroprotection from brain injury. Neurosci. Res. 2011, 71, 107–113. [Google Scholar] [CrossRef]
  31. Simon, D.W.; McGeachy, M.J.; Bayir, H.; Clark, R.S.; Loane, D.J.; Kochanek, P.M. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat. Rev. Neurol. 2017, 13, 171–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Gardner, R.C.; Byers, A.L.; Barnes, D.E.; Li, Y.; Boscardin, J.; Yaffe, K. Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study. Neurology 2018, 90, e1771–e1779. [Google Scholar] [CrossRef]
  33. Acosta, S.A.; Diamond, D.M.; Wolfe, S.; Tajiri, N.; Shinozuka, K.; Ishikawa, H.; Hernandez, D.G.; Sanberg, P.R.; Kaneko, Y.; Borlongan, C.V. Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury. PLoS ONE 2013, 8, e81585. [Google Scholar] [CrossRef] [PubMed]
  34. Acosta, S.A.; Tajiri, N.; Shinozuka, K.; Ishikawa, H.; Grimmig, B.; Diamond, D.M.; Sanberg, P.R.; Bickford, P.C.; Kaneko, Y.; Borlongan, C.V. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS ONE 2013, 8, e53376. [Google Scholar] [CrossRef]
  35. Acosta, S.A.; Tajiri, N.; Shinozuka, K.; Ishikawa, H.; Sanberg, P.R.; Sanchez-Ramos, J.; Song, S.; Kaneko, Y.; Borlongan, C.V. Combination therapy of human umbilical cord blood cells and granulocyte colony stimulating factor reduces histopathological and motor impairments in an experimental model of chronic traumatic brain injury. PLoS ONE 2014, 9, e90953. [Google Scholar] [CrossRef] [PubMed]
  36. Lucas, S.M.; Rothwell, N.J.; Gibson, R.M. The role of inflammation in CNS injury and disease. Br. J. Pharmacol. 2006, 147, S232–S240. [Google Scholar] [CrossRef] [Green Version]
  37. Lozano, D.; Gonzales-Portillo, G.S.; Acosta, S.; de la Pena, I.; Tajiri, N.; Kaneko, Y.; Borlongan, C.V. Neuroinflammatory responses to traumatic brain injury: Etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr. Dis. Treat. 2015, 11, 97. [Google Scholar]
  38. Yang, Y.; Ye, Y.; Su, X.; He, J.; Bai, W.; He, X. MSCs-derived exosomes and neuroinflammation, neurogenesis and therapy of traumatic brain injury. Front. Cell. Neurosci. 2017, 11, 55. [Google Scholar] [CrossRef] [Green Version]
  39. Quan, F.S.; Chen, J.; Zhong, Y.; Ren, W.Z. Comparative effect of immature neuronal or glial cell transplantation on motor functional recovery following experimental traumatic brain injury in rats. Exp. Ther. Med. 2016, 12, 1671–1680. [Google Scholar] [CrossRef] [Green Version]
  40. Karve, I.P.; Taylor, J.M.; Crack, P.J. The contribution of astrocytes and microglia to traumatic brain injury. Br. J. Pharmacol. 2016, 173, 692–702. [Google Scholar] [CrossRef] [Green Version]
  41. Woodcock, T.; Morganti-Kossmann, M.C. The role of markers of inflammation in traumatic brain injury. Front. Neurol. 2013, 4, 18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Hellewell, S.; Semple, B.D.; Morganti-Kossmann, M.C. Therapies negating neuroinflammation after brain trauma. Brain Res. 2016, 1640, 36–56. [Google Scholar] [CrossRef] [PubMed]
  43. Bergold, P.J. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp. Neurol. 2016, 275 Pt 3, 367–380. [Google Scholar] [CrossRef]
  44. Ziebell, J.M.; Morganti-Kossmann, M.C. Involvement of pro-and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 2010, 7, 22–30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Biber, K.; Neumann, H.; Inoue, K.; Boddeke, H.W. Neuronal ‘On’and ‘Off’signals control microglia. Trends Neurosci. 2007, 30, 596–602. [Google Scholar] [CrossRef]
  46. Aloisi, F. Immune function of microglia. Glia 2001, 36, 165–179. [Google Scholar] [CrossRef]
  47. Johnson, V.E.; Stewart, W.; Smith, D.H. Axonal pathology in traumatic brain injury. Exp. Neurol. 2013, 246, 35–43. [Google Scholar] [CrossRef] [Green Version]
  48. Donat, C.K.; Scott, G.; Gentleman, S.M.; Sastre, M. Microglial Activation in Traumatic Brain Injury. Front. Aging Neurosci. 2017, 9, 208. [Google Scholar] [CrossRef] [Green Version]
  49. Tomaiuolo, F.; Bivona, U.; Lerch, J.P.; Di Paola, M.; Carlesimo, G.A.; Ciurli, P.; Matteis, M.; Cecchetti, L.; Forcina, A.; Silvestro, D.; et al. Memory and anatomical change in severe non missile traumatic brain injury: ∼1 vs. ∼8years follow-up. Brain Res. Bull. 2012, 87, 373–382. [Google Scholar] [CrossRef]
  50. Wilde, E.A.; Chu, Z.; Bigler, E.D.; Hunter, J.V.; Fearing, M.A.; Hanten, G.; Newsome, M.R.; Scheibel, R.S.; Li, X.; Levin, H.S. Diffusion tensor imaging in the corpus callosum in children after moderate to severe traumatic brain injury. J. Neurotrauma 2006, 23, 1412–1426. [Google Scholar] [CrossRef]
  51. Bigler, E. Traumatic brain injury, neuroimaging, and neurodegeneration. Front. Hum. Neurosci. 2013, 7, 395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Stocchetti, N.; Zanier, E.R. Chronic impact of traumatic brain injury on outcome and quality of life: A narrative review. Crit. Care 2016, 20, 148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Neumann, H.; Kotter, M.R.; Franklin, R.J. Debris clearance by microglia: An essential link between degeneration and regeneration. Brain 2009, 132, 288–295. [Google Scholar] [CrossRef]
  54. Ramlackhansingh, A.F.; Brooks, D.J.; Greenwood, R.J.; Bose, S.K.; Turkheimer, F.E.; Kinnunen, K.M.; Gentleman, S.; Heckemann, R.A.; Gunanayagam, K.; Gelosa, G.; et al. Inflammation after trauma: Microglial activation and traumatic brain injury. Ann. Neurol. 2011, 70, 374–383. [Google Scholar] [CrossRef] [PubMed]
  55. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef] [PubMed]
  56. Bianco, P.; Robey, P.G.; Simmons, P.J. Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell 2008, 2, 313–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Pachon-Pena, G.; Yu, G.; Tucker, A.; Wu, X.; Vendrell, J.; Bunnell, B.A.; Gimble, J.M. Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. J. Cell Physiol. 2011, 226, 843–851. [Google Scholar] [CrossRef] [Green Version]
  58. Talwadekar, M.D.; Kale, V.P.; Limaye, L.S. Placenta-derived mesenchymal stem cells possess better immunoregulatory properties compared to their cord-derived counterparts-a paired sample study. Sci. Rep. 2015, 5, 15784. [Google Scholar] [CrossRef] [Green Version]
  59. Gala, K.; Burdzinska, A.; Idziak, M.; Makula, J.; Paczek, L. Characterization of bone-marrow-derived rat mesenchymal stem cells depending on donor age. Cell Biol. Int. 2011, 35, 1055–1062. [Google Scholar] [CrossRef]
  60. Joyce, N.; Annett, G.; Wirthlin, L.; Olson, S.; Bauer, G.; Nolta, J.A. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen. Med. 2010, 5, 933–946. [Google Scholar] [CrossRef] [Green Version]
  61. Azizi, S.A.; Stokes, D.; Augelli, B.J.; DiGirolamo, C.; Prockop, D.J. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—Similarities to astrocyte grafts. Proc. Natl. Acad. Sci. USA 1998, 95, 3908–3913. [Google Scholar] [CrossRef] [Green Version]
  62. Galindo, L.T.; Filippo, T.R.; Semedo, P.; Ariza, C.B.; Moreira, C.M.; Camara, N.O.; Porcionatto, M.A. Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol. Res. Int. 2011, 2011, 564089. [Google Scholar] [CrossRef] [Green Version]
  63. Kim, H.-J.; Lee, J.-H.; Kim, S.-H. Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: Secretion of neurotrophic factors and inhibition of apoptosis. J. Neurotrauma 2010, 27, 131–138. [Google Scholar] [CrossRef] [PubMed]
  64. Opydo-Chanek, M. Bone marrow stromal cells in traumatic brain injury (TBI) therapy: True perspective or false hope? Acta Neurobiol. Exp. 2007, 67, 187. [Google Scholar]
  65. Gonzalez, M.E.; Martin, E.E.; Anwar, T.; Arellano-Garcia, C.; Medhora, N.; Lama, A.; Chen, Y.-C.; Tanager, K.S.; Yoon, E.; Kidwell, K.M. Mesenchymal stem cell-induced DDR2 mediates stromal-breast cancer interactions and metastasis growth. Cell Rep. 2017, 18, 1215–1228. [Google Scholar] [CrossRef]
  66. Huang, J.; Basu, S.; Zhao, X.; Chien, S.; Fang, M.; Oehler, V.; Appelbaum, F.; Becker, P. Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration. Blood Cancer J. 2015, 5, e302. [Google Scholar] [CrossRef] [PubMed]
  67. He, L.; Zhao, F.; Zheng, Y.; Wan, Y.; Song, J. Loss of interactions between p53 and survivin gene in mesenchymal stem cells after spontaneous transformation in vitro. Int. J. Biochem. Cell Biol. 2016, 75, 74–84. [Google Scholar] [CrossRef] [PubMed]
  68. Chen, X.; Katakowski, M.; Li, Y.; Lu, D.; Wang, L.; Zhang, L.; Chen, J.; Xu, Y.; Gautam, S.; Mahmood, A.; et al. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: Growth factor production. J. Neurosci. Res. 2002, 69, 687–691. [Google Scholar] [CrossRef]
  69. Meyerrose, T.; Olson, S.; Pontow, S.; Kalomoiris, S.; Jung, Y.; Annett, G.; Bauer, G.; Nolta, J.A. Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv. Drug Deliv. Rev. 2010, 62, 1167–1174. [Google Scholar] [CrossRef] [Green Version]
  70. Mahmood, A.; Lu, D.; Chopp, M. Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J. Neurotrauma 2004, 21, 33–39. [Google Scholar] [CrossRef]
  71. Mahmood, A.; Lu, D.; Lu, M.; Chopp, M. Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery 2003, 53, 697–702. [Google Scholar] [CrossRef] [PubMed]
  72. Mahmood, A.; Lu, D.; Qu, C.; Goussev, A.; Chopp, M. Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats. J. Neurosurg. 2006, 104, 272–277. [Google Scholar] [CrossRef] [PubMed]
  73. Dekmak, A.; Mantash, S.; Shaito, A.; Toutonji, A.; Ramadan, N.; Ghazale, H.; Kassem, N.; Darwish, H.; Zibara, K. Stem cells and combination therapy for the treatment of traumatic brain injury. Behav. Brain Res. 2018, 340, 49–62. [Google Scholar] [CrossRef] [PubMed]
  74. Chang, C.P.; Chio, C.C.; Cheong, C.U.; Chao, C.M.; Cheng, B.C.; Lin, M.T. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin. Sci. (Lond.) 2013, 124, 165–176. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, Z.X.; Guan, L.X.; Zhang, K.; Zhang, Q.; Dai, L.J. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy 2008, 10, 134–139. [Google Scholar] [CrossRef] [PubMed]
  76. Walker, P.A.; Shah, S.K.; Harting, M.T.; Cox, C.S., Jr. Progenitor cell therapies for traumatic brain injury: Barriers and opportunities in translation. Dis. Model Mech. 2009, 2, 23–38. [Google Scholar] [CrossRef] [Green Version]
  77. Chuang, T.J.; Lin, K.C.; Chio, C.C.; Wang, C.C.; Chang, C.P.; Kuo, J.R. Effects of secretome obtained from normoxia-preconditioned human mesenchymal stem cells in traumatic brain injury rats. J. Trauma Acute Care Surg. 2012, 73, 1161–1167. [Google Scholar] [CrossRef] [Green Version]
  78. Zhang, R.; Liu, Y.; Yan, K.; Chen, L.; Chen, X.R.; Li, P.; Chen, F.F.; Jiang, X.D. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J. Neuroinflammation 2013, 10, 106. [Google Scholar] [CrossRef] [Green Version]
  79. Lin, C.-H.; Lin, W.; Su, Y.-C.; Cheng-Yo Hsuan, Y.; Chen, Y.-C.; Chang, C.-P.; Chou, W.; Lin, K.-C. Modulation of parietal cytokine and chemokine gene profiles by mesenchymal stem cell as a basis for neurotrauma recovery. J. Formos. Med. Assoc. 2019, 118, 1661–1673. [Google Scholar] [CrossRef]
  80. Barker, G.R.; Warburton, E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 2011, 31, 10721–10731. [Google Scholar] [CrossRef] [Green Version]
  81. Gao, X.; Deng-Bryant, Y.; Cho, W.; Carrico, K.M.; Hall, E.D.; Chen, J. Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury. J. Neurosci. Res. 2008, 86, 2258–2270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Grady, M.S.; Charleston, J.S.; Maris, D.; Witgen, B.M.; Lifshitz, J. Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: Analysis by stereological estimation. J. Neurotrauma 2003, 20, 929–941. [Google Scholar] [CrossRef] [PubMed]
  83. Shahror, R.A.; Linares, G.R.; Wang, Y.; Hsueh, S.C.; Wu, C.C.; Chuang, D.M.; Chiang, Y.H.; Chen, K.Y. Transplantation of Mesenchymal Stem Cells Overexpressing Fibroblast Growth Factor 21 Facilitates Cognitive Recovery and Enhances Neurogenesis in a Mouse Model of Traumatic Brain Injury. J. Neurotrauma 2020, 37, 14–26. [Google Scholar] [CrossRef] [PubMed]
  84. Ibrahim, S.; Hu, W.; Wang, X.; Gao, X.; He, C.; Chen, J. Traumatic Brain Injury Causes Aberrant Migration of Adult-Born Neurons in the Hippocampus. Sci. Rep. 2016, 6, 21793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Golarai, G.; Greenwood, A.C.; Feeney, D.M.; Connor, J.A. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J. Neurosci. 2001, 21, 8523–8537. [Google Scholar] [CrossRef]
  86. Kharatishvili, I.; Nissinen, J.P.; McIntosh, T.K.; Pitkänen, A. A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats. Neuroscience 2006, 140, 685–697. [Google Scholar] [CrossRef]
  87. Babb, T.L.; Kupfer, W.R.; Pretorius, J.K.; Crandall, P.H.; Levesque, M.F. Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience 1991, 42, 351–363. [Google Scholar] [CrossRef]
  88. Atkins, C.M.; Truettner, J.S.; Lotocki, G.; Sanchez-Molano, J.; Kang, Y.; Alonso, O.F.; Sick, T.J.; Dietrich, W.D.; Bramlett, H.M. Post-traumatic seizure susceptibility is attenuated by hypothermia therapy. Eur. J. Neurosci. 2010, 32, 1912–1920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Bramlett, H.M.; Dietrich, W.D. Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes. J. Neurotrauma 2015, 32, 1834–1848. [Google Scholar] [CrossRef]
  90. Swartz, B.E.; Houser, C.R.; Tomiyasu, U.; Walsh, G.O.; DeSalles, A.; Rich, J.R.; Delgado-Escueta, A. Hippocampal cell loss in posttraumatic human epilepsy. Epilepsia 2006, 47, 1373–1382. [Google Scholar] [CrossRef]
  91. Chen, J.; Hu, J.; Liu, H.; Xiong, Y.; Zou, Y.; Huang, W.; Shao, M.; Wu, J.; Yu, L.; Wang, X.; et al. FGF21 Protects the Blood-Brain Barrier by Upregulating PPARgamma via FGFR1/beta-klotho after Traumatic Brain Injury. J. Neurotrauma 2018, 35, 2091–2103. [Google Scholar] [CrossRef] [PubMed]
  92. Munoz, J.R.; Stoutenger, B.R.; Robinson, A.P.; Spees, J.L.; Prockop, D.J. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc. Natl. Acad. Sci. USA 2005, 102, 18171–18176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Lu, D.; Mahmood, A.; Wang, L.; Li, Y.; Lu, M.; Chopp, M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 2001, 12, 559–563. [Google Scholar] [CrossRef] [PubMed]
  94. Mahmood, A.; Lu, D.; Wang, L.; Li, Y.; Lu, M.; Chopp, M. Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 2001, 49, 1196–1204. [Google Scholar] [PubMed]
  95. Jackson, J.S.; Golding, J.P.; Chapon, C.; Jones, W.A.; Bhakoo, K.K. Homing of stem cells to sites of inflammatory brain injury after intracerebral and intravenous administration: A longitudinal imaging study. Stem Cell Res. Ther. 2010, 1, 17. [Google Scholar] [CrossRef] [Green Version]
  96. Chapel, A.; Bertho, J.M.; Bensidhoum, M.; Fouillard, L.; Young, R.G.; Frick, J.; Demarquay, C.; Cuvelier, F.; Mathieu, E.; Trompier, F.; et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J. Gene Med. 2003, 5, 1028–1038. [Google Scholar] [CrossRef]
  97. Devine, S.M.; Cobbs, C.; Jennings, M.; Bartholomew, A.; Hoffman, R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003, 101, 2999–3001. [Google Scholar] [CrossRef]
  98. Kraitchman, D.L.; Tatsumi, M.; Gilson, W.D.; Ishimori, T.; Kedziorek, D.; Walczak, P.; Segars, W.P.; Chen, H.H.; Fritzges, D.; Izbudak, I.; et al. Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction. Circulation 2005, 112, 1451–1461. [Google Scholar] [CrossRef] [Green Version]
  99. Jin, S.-Z.; Liu, B.-R.; Xu, J.; Gao, F.-L.; Hu, Z.-J.; Wang, X.-H.; Pei, F.-H.; Hong, Y.; Hu, H.-Y.; Han, M.-Z. Ex vivo-expanded bone marrow stem cells home to the liver and ameliorate functional recovery in a mouse model of acute hepatic injury. Hepatobiliary Pancreatic Dis. Int. 2012, 11, 66–73. [Google Scholar] [CrossRef]
  100. Steingen, C.; Brenig, F.; Baumgartner, L.; Schmidt, J.; Schmidt, A.; Bloch, W. Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. J. Mol. Cell Cardiol. 2008, 44, 1072–1084. [Google Scholar] [CrossRef]
  101. Chamberlain, G.; Wright, K.; Rot, A.; Ashton, B.; Middleton, J. Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: Comparison with human. PLoS ONE 2008, 3, e2934. [Google Scholar] [CrossRef] [PubMed]
  102. Ponte, A.L.; Marais, E.; Gallay, N.; Langonné, A.; Delorme, B.; Hérault, O.; Charbord, P.; Domenech, J. The in vitro migration capacity of human bone marrow mesenchymal stem cells: Aomparison of chemokine and growth factor chemotactic activities. Stem Cells 2007, 25, 1737–1745. [Google Scholar] [CrossRef] [PubMed]
  103. Chamberlain, G.; Smith, H.; Rainger, G.E.; Middleton, J. Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: Effects of chemokines and shear. PLoS ONE 2011, 6, e25663. [Google Scholar] [CrossRef] [PubMed]
  104. De Becker, A.; Van Hummelen, P.; Bakkus, M.; Vande Broek, I.; De Wever, J.; De Waele, M.; Van Riet, I. Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica 2007, 92, 440–449. [Google Scholar] [CrossRef] [PubMed]
  105. Menge, T.; Zhao, Y.; Zhao, J.; Wataha, K.; Gerber, M.; Zhang, J.; Letourneau, P.; Redell, J.; Shen, L.; Wang, J.; et al. Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury. Sci. Transl. Med. 2012, 4, 161ra150. [Google Scholar] [CrossRef] [Green Version]
  106. Lee, R.H.; Pulin, A.A.; Seo, M.J.; Kota, D.J.; Ylostalo, J.; Larson, B.L.; Semprun-Prieto, L.; Delafontaine, P.; Prockop, D.J. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009, 5, 54–63. [Google Scholar] [CrossRef] [Green Version]
  107. Naldini, L.; Blomer, U.; Gage, F.H.; Trono, D.; Verma, I.M. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc. Natl. Acad. Sci. USA 1996, 93, 11382–11388. [Google Scholar] [CrossRef] [Green Version]
  108. Schroder, A.R.; Shinn, P.; Chen, H.; Berry, C.; Ecker, J.R.; Bushman, F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002, 110, 521–529. [Google Scholar] [CrossRef] [Green Version]
  109. Nienhuis, A.W.; Dunbar, C.E.; Sorrentino, B.P. Genotoxicity of retroviral integration in hematopoietic cells. Molecules 2006, 13, 1031–1049. [Google Scholar] [CrossRef]
  110. Dewey, R.; Morrissey, G.; Cowsill, C.; Stone, D.; Bolognani, F.; Dodd, N.; Southgate, T.; Klatzmann, D.; Lassmann, H.; Castro, M. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials. Nat. Med. 1999, 5, 1256–1263. [Google Scholar] [CrossRef]
  111. Chen, L.; Xu, Y.; Zhao, J.; Zhang, Z.; Yang, R.; Xie, J.; Liu, X.; Qi, S. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS ONE 2014, 9, e96161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Jiang, C.; Liu, J.; Zhao, J.; Xiao, L.; An, S.; Gou, Y.; Quan, H.; Cheng, Q.; Zhang, Y.; He, W. Effects of hypoxia on the immunomodulatory properties of human Gingiva–derived mesenchymal stem cells. J. Dent. Res. 2015, 94, 69–77. [Google Scholar] [CrossRef] [PubMed]
  113. McCrudden, C.M.; McCarthy, H.O. Cancer gene therapy–key biological concepts in the design of multifunctional non-viral delivery systems. In Gene Therapy-Tools and Potential Applications; IntechOpen: London, UK, 2013. [Google Scholar]
  114. Stenler, S.; Blomberg, P.; Smith, C.I. Safety and efficacy of DNA vaccines: Plasmids vs. minicircles. Hum. Vaccin. Immunother. 2014, 10, 1306–1308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Schafer, R.; Spohn, G.; Baer, P.C. Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Can Preconditioning Strategies Improve Therapeutic Efficacy? Transfus. Med. Hemother. 2016, 43, 256–267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Nakajima, M.; Nito, C.; Sowa, K.; Suda, S.; Nishiyama, Y.; Nakamura-Takahashi, A.; Nitahara-Kasahara, Y.; Imagawa, K.; Hirato, T.; Ueda, M.; et al. Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke. Mol. Methods Clin. Dev. 2017, 6, 102–111. [Google Scholar] [CrossRef] [Green Version]
  117. Manning, E.; Pham, S.; Li, S.; Vazquez-Padron, R.I.; Mathew, J.; Ruiz, P.; Salgar, S.K. Interleukin-10 delivery via mesenchymal stem cells: A novel gene therapy approach to prevent lung ischemia-reperfusion injury. Hum. Gene 2010, 21, 713–727. [Google Scholar] [CrossRef]
  118. Choi, J.J.; Yoo, S.A.; Park, S.J.; Kang, Y.J.; Kim, W.U.; Oh, I.H.; Cho, C.S. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice. Clin. Exp. Immunol. 2008, 153, 269–276. [Google Scholar] [CrossRef]
  119. Liao, W.; Pham, V.; Liu, L.; Riazifar, M.; Pone, E.J.; Zhang, S.X.; Ma, F.; Lu, M.; Walsh, C.M.; Zhao, W. Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis. Biomaterials 2016, 77, 87–97. [Google Scholar] [CrossRef] [Green Version]
  120. Min, C.K.; Kim, B.G.; Park, G.; Cho, B.; Oh, I.H. IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transpl. 2007, 39, 637–645. [Google Scholar] [CrossRef] [Green Version]
  121. Peruzzaro, S.T.; Andrews, M.M.M.; Al-Gharaibeh, A.; Pupiec, O.; Resk, M.; Story, D.; Maiti, P.; Rossignol, J.; Dunbar, G.L. Transplantation of mesenchymal stem cells genetically engineered to overexpress interleukin-10 promotes alternative inflammatory response in rat model of traumatic brain injury. J. Neuroinflammation 2019, 16, 2. [Google Scholar] [CrossRef]
  122. Shahror, R.A.; Ali, A.A.A.; Wu, C.C.; Chiang, Y.H.; Chen, K.Y. Enhanced Homing of Mesenchymal Stem Cells Overexpressing Fibroblast Growth Factor 21 to Injury Site in a Mouse Model of Traumatic Brain Injury. Int. J. Mol. Sci. 2019, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Hu, S.; Cao, S.; Liu, J. Role of angiopoietin-2 in the cardioprotective effect of fibroblast growth factor 21 on ischemia/reperfusion-induced injury in H9c2 cardiomyocytes. Exp. Med. 2017, 14, 771–779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Wang, X.; Zhu, Y.; Sun, C.; Wang, T.; Shen, Y.; Cai, W.; Sun, J.; Chi, L.; Wang, H.; Song, N.; et al. Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/beta-Catenin Pathway in Skin Fibroblasts. Front. Pharm. 2017, 8, 32. [Google Scholar] [CrossRef] [Green Version]
  125. Song, Y.; Ding, J.; Jin, R.; Jung, J.; Li, S.; Yang, J.; Wang, A.; Li, Z. Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration. Mol. Med. Rep. 2016, 13, 3619–3626. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Yuan, Y.; Pan, S.; Sun, Z.; Dan, Q.; Liu, J. Brain-derived neurotrophic factor-modified umbilical cord mesenchymal stem cell transplantation improves neurological deficits in rats with traumatic brain injury. Int. J. Neurosci. 2014, 124, 524–531. [Google Scholar] [CrossRef]
  127. Heile, A.M.; Wallrapp, C.; Klinge, P.M.; Samii, A.; Kassem, M.; Silverberg, G.; Brinker, T. Cerebral transplantation of encapsulated mesenchymal stem cells improves cellular pathology after experimental traumatic brain injury. Neurosci. Lett. 2009, 463, 176–181. [Google Scholar] [CrossRef]
  128. Zou, L.; Huang, L.; Hayes, R.; Black, C.; Qiu, Y.; Perez-Polo, J.; Le, W.; Clifton, G.; Yang, K. Liposome-mediated NGF gene transfection following neuronal injury: Potential therapeutic applications. Gene Ther. 1999, 6, 994–1005. [Google Scholar] [CrossRef] [Green Version]
  129. Philips, M.F.; Mattiasson, G.; Wieloch, T.; Björklund, A.; Johansson, B.B.; Tomasevic, G.; Martínez-Serrano, A.; Lenzlinger, P.M.; Sinson, G.; Grady, M.S. Neuroprotective and behavioral efficacy of nerve growth factor—Transfected hippocampal progenitor cell transplants after experimental traumatic brain injury. J. Neurosurg. 2001, 94, 765–774. [Google Scholar] [CrossRef]
  130. Kim, C.D.; Shin, H.K.; Lee, H.S.; Lee, J.H.; Lee, T.H.; Hong, K.W. Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction. Am. J. Physiol. Heart Circ. Physiol. 2002, 282, H1836–H1842. [Google Scholar] [CrossRef] [Green Version]
  131. Tang, C.; Shan, Y.; Hu, Y.; Fang, Z.; Tong, Y.; Chen, M.; Wei, X.; Fu, X.; Xu, X. FGF2 Attenuates Neural Cell Death via Suppressing Autophagy after Rat Mild Traumatic Brain Injury. Stem Cells Int. 2017, 2017, 2923182. [Google Scholar] [CrossRef] [Green Version]
  132. Yoshimura, S.; Teramoto, T.; Whalen, M.J.; Irizarry, M.C.; Takagi, Y.; Qiu, J.; Harada, J.; Waeber, C.; Breakefield, X.O.; Moskowitz, M.A. FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. J. Clin. Investig. 2003, 112, 1202–1210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Khalin, I.; Alyautdin, R.; Wong, T.W.; Gnanou, J.; Kocherga, G.; Kreuter, J. Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury. Drug Deliv. 2016, 23, 3520–3528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Chan, S.J.; Love, C.; Spector, M.; Cool, S.M.; Nurcombe, V.; Lo, E.H. Endogenous regeneration: Engineering growth factors for stroke. Neurochem. Int. 2017, 107, 57–65. [Google Scholar] [CrossRef] [PubMed]
  135. Redell, J.B.; Moore, A.N.; Ward III, N.H.; Hergenroeder, G.W.; Dash, P.K. Human traumatic brain injury alters plasma microRNA levels. J. Neurotrauma 2010, 27, 2147–2156. [Google Scholar] [CrossRef] [PubMed]
  136. Redell, J.B.; Liu, Y.; Dash, P.K. Traumatic brain injury alters expression of hippocampal microRNAs: Potential regulators of multiple pathophysiological processes. J. Neurosci. Res. 2009, 87, 1435–1448. [Google Scholar] [CrossRef]
  137. Wang, S.; Cheng, H.; Dai, G.; Wang, X.; Hua, R.; Liu, X.; Wang, P.; Chen, G.; Yue, W.; An, Y. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013, 1532, 76–84. [Google Scholar] [CrossRef]
  138. Palfi, S.; Gurruchaga, J.M.; Lepetit, H.; Howard, K.; Ralph, G.S.; Mason, S.; Gouello, G.; Domenech, P.; Buttery, P.C.; Hantraye, P. Long-term follow-up of a phase I/II study of ProSavin, a lentiviral vector gene therapy for Parkinson’s disease. Hum. Gene Ther. Clin. Dev. 2018, 29, 148–155. [Google Scholar] [CrossRef]
  139. Hwu, W.-L.; Muramatsu, S.-I.; Tseng, S.-H.; Tzen, K.-Y.; Lee, N.-C.; Chien, Y.-H.; Snyder, R.O.; Byrne, B.J.; Tai, C.-H.; Wu, R.-M. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci. Transl. Med. 2012, 4, 134ra161. [Google Scholar] [CrossRef] [Green Version]
  140. LeWitt, P.A.; Rezai, A.R.; Leehey, M.A.; Ojemann, S.G.; Flaherty, A.W.; Eskandar, E.N.; Kostyk, S.K.; Thomas, K.; Sarkar, A.; Siddiqui, M.S. AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011, 10, 309–319. [Google Scholar] [CrossRef]
  141. Mittermeyer, G.; Christine, C.W.; Rosenbluth, K.H.; Baker, S.L.; Starr, P.; Larson, P.; Kaplan, P.L.; Forsayeth, J.; Aminoff, M.J.; Bankiewicz, K.S. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum. Gene Ther. 2012, 23, 377–381. [Google Scholar] [CrossRef] [Green Version]
  142. Stoessl, A.J. Gene therapy for Parkinson’s disease: A step closer? Lancet 2014, 383, 1107–1109. [Google Scholar] [CrossRef]
  143. Niethammer, M.; Tang, C.C.; Vo, A.; Nguyen, N.; Spetsieris, P.; Dhawan, V.; Ma, Y.; Small, M.; Feigin, A.; During, M.J. Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity. Sci. Transl. Med. 2018, 10, eaau0713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. Traumatic brain injury (TBI) pathobiology. The primary insult of TBI results in blood-brain barrier (BBB) breakdown and necrotic death of neurons. Following the BBB breakdown, perfusion, and increased edema, leading to increased hypoxia results in neural injury and death. Aberrant neurotransmitter release from the injured neurons leads to excitotoxic cell injury and death. Astroglial and microglial cell activation releases numerous cytokines and chemokines, both leading to chronic inflammation. The further cellular injury occurs due to oligodendrocyte death and axonal death. Abbreviations: BBB, blood-brain barrier; CBF, cerebral blood flow; TBI, traumatic brain injury.
Figure 1. Traumatic brain injury (TBI) pathobiology. The primary insult of TBI results in blood-brain barrier (BBB) breakdown and necrotic death of neurons. Following the BBB breakdown, perfusion, and increased edema, leading to increased hypoxia results in neural injury and death. Aberrant neurotransmitter release from the injured neurons leads to excitotoxic cell injury and death. Astroglial and microglial cell activation releases numerous cytokines and chemokines, both leading to chronic inflammation. The further cellular injury occurs due to oligodendrocyte death and axonal death. Abbreviations: BBB, blood-brain barrier; CBF, cerebral blood flow; TBI, traumatic brain injury.
Ijms 21 04051 g001
Figure 2. Summary of the therapeutic effects of mesenchymal stem cells (MSCs) in TBI. Prior to transplantation, MSCs can be isolated easily from different sources such as adipose tissue, placenta and umbilical cord, bone marrow, or dental pulp. Transplantation of MSCs can increase synaptogenesis, neurogenesis, angiogenesis, and neurotrophic factors at the injured brain tissue after TBI insults. Furthermore, MSCs can inhibit neuroinflammation, and apoptosis and thereby promote neuroprotective or neurorestorative effects, as well as improve functional outcomes after TBI.
Figure 2. Summary of the therapeutic effects of mesenchymal stem cells (MSCs) in TBI. Prior to transplantation, MSCs can be isolated easily from different sources such as adipose tissue, placenta and umbilical cord, bone marrow, or dental pulp. Transplantation of MSCs can increase synaptogenesis, neurogenesis, angiogenesis, and neurotrophic factors at the injured brain tissue after TBI insults. Furthermore, MSCs can inhibit neuroinflammation, and apoptosis and thereby promote neuroprotective or neurorestorative effects, as well as improve functional outcomes after TBI.
Ijms 21 04051 g002
Figure 3. Improving MSCs’ therapeutic potential for TBI via genetic modification. Illustration of possible MSC sources in humans and the possible targets for genetic modification in vitro. Following transplantation, the genetically modified MSCs are able to improve the homing, survival, and paracrine effects of MSCs, enhance neurogenesis, and enable neuroprotection and immunomodulation at the injury site in TBI.
Figure 3. Improving MSCs’ therapeutic potential for TBI via genetic modification. Illustration of possible MSC sources in humans and the possible targets for genetic modification in vitro. Following transplantation, the genetically modified MSCs are able to improve the homing, survival, and paracrine effects of MSCs, enhance neurogenesis, and enable neuroprotection and immunomodulation at the injury site in TBI.
Ijms 21 04051 g003

Share and Cite

MDPI and ACS Style

Shahror, R.A.; Wu, C.-C.; Chiang, Y.-H.; Chen, K.-Y. Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI. Int. J. Mol. Sci. 2020, 21, 4051.

AMA Style

Shahror RA, Wu C-C, Chiang Y-H, Chen K-Y. Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI. International Journal of Molecular Sciences. 2020; 21(11):4051.

Chicago/Turabian Style

Shahror, Rami Ahmad, Chung-Che Wu, Yung-Hsiao Chiang, and Kai-Yun Chen. 2020. "Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI" International Journal of Molecular Sciences 21, no. 11: 4051.

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