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Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 55911

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Special Issue Editor

Dr. Kyung-Rok Yu

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Guest Editor

Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
Interests: immunomodulatory function of MSCs; MSC-based therapy; exosome-based therapy; adult stem cell aging; hematopoiesis; inflammaging

Special Issue Information

Dear Colleagues,

The area of mesenchymal stem/stromal cell (MSC)-based cell therapy has been actively explored as an alternative therapeutic option for a variety of immune-mediated diseases. MSCs play a significant role in tissue repair and regeneration through their multilineage differentiation potential and/or immunomodulatory properties, regulating both innate and adaptive immunity. Although heterogeneity and cellular aging process during large-scale culture can be the Achilles’ heel of MSC-based therapy, to date, 1073 MSC-based clinical trials, either complete or ongoing, appear in the database of the NIH. Furthermore, recent advances of exosome research have demonstrated that the therapeutic effects of MSCs can be mediated by MSC-derived exosomes (MSC-Exo) as they contain various immunomodulatory factors, such as cytokines, growth factors, signaling lipids, and coding/noncoding RNAs. Cell-free therapy with MSC-Exo may provide some advantages over parent MSCs, such as lower immunogenicity or lower risk of infusion toxicities. The present Special Issue aims to deepen our understanding of the mechanism of in vitro/in vivo action of exogenously administered MSCs or MSC-Exo, including molecular targets, mode of action, pharmacokinetics, and safety.

Dr. Kyung-Rok Yu
Guest Editor

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Keywords

mesenchymal stem cell-based therapy
mesenchymal stem cell-derived exosomes
exosome-based therapy
immunomodulation
regenerative medicine
extracellular vesicles
disease model

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Published Papers (10 papers)

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Research

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16 pages, 4457 KiB

Open AccessArticle

Serum Proteins, HMMR, NXPH4, PITX1 and THBS4; A Panel of Biomarkers for Early Diagnosis of Hepatocellular Carcinoma

by Jung Woo Eun, Jeong Won Jang, Hee Doo Yang, Jooyoung Kim, Sang Yean Kim, Min Jeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Young Min Ahn, Won Sang Park and Suk Woo Nam

J. Clin. Med. 2022, 11(8), 2128; https://doi.org/10.3390/jcm11082128 - 11 Apr 2022

Cited by 11 | Viewed by 2701

Abstract

The high morbidity rate of hepatocellular carcinoma (HCC) is mainly linked to late diagnosis. Early diagnosis of this leading cause of mortality is therefore extremely important. We designed a gene selection strategy to identify potential secretory proteins by predicting signal peptide cleavage sites in amino acid sequences derived from transcriptome data of human multistage HCC comprising chronic hepatitis, liver cirrhosis and early and overt HCCs. The gene selection process was validated by the detection of molecules in the serum of HCC patients. From the computational approaches, 10 gene elements were suggested as potent candidate secretory markers for detecting HCC patients. ELISA testing of serum showed that hyaluronan mediated motility receptor (HMMR), neurexophilin 4 (NXPH4), paired like homeodomain 1 (PITX1) and thrombospondin 4 (THBS4) are early-stage HCC diagnostic markers with superior predictive capability in a large cohort of HCC patients. In the assessment of differential diagnostic accuracy, receiver operating characteristic curve analyses showed that HMMR and THBS4 were superior to α-fetoprotein (AFP) in diagnosing HCC, as evidenced by the high area under the curve, sensitivity, specificity, accuracy and other values. In addition, comparative analysis of all four markers and AFP combinations demonstrated that HMMR-PITX1-AFP and HMMR-NXPH4-PITX1 trios were the optimal combinations for reaching 100% accuracy in HCC diagnosis. Serum proteins HMMR, NXPH4, PITX1 and THBS4 can complement measurement of AFP in diagnosing HCC and improve identification of patients with AFP-negative HCC as well as discriminate HCC from non-malignant chronic liver disease. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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18 pages, 2731 KiB

Open AccessArticle

Nasal Turbinate Mesenchymal Stromal Cells Preserve Characteristics of Their Neural Crest Origin and Exert Distinct Paracrine Activity

by Hyun-Jee Kim, Sungho Shin, Seon-Yeong Jeong, Sun-Ung Lim, Dae-Won Lee, Yunhee-Kim Kwon, Jiyeon Kang, Sung-Won Kim, Chan-Kwon Jung, Cheolju Lee and Il-Hoan Oh

J. Clin. Med. 2021, 10(8), 1792; https://doi.org/10.3390/jcm10081792 - 20 Apr 2021

Cited by 4 | Viewed by 2887

Abstract

The sources of mesenchymal stromal cells (MSCs) for cell therapy trials are expanding, increasing the need for their characterization. Here, we characterized multi-donor, turbinate-derived MSCs (TB-MSCs) that develop from the neural crest, and compared them to bone marrow-derived MSCs (BM-MSCs). TB-MSCs had higher proliferation potential and higher self-renewal of colony forming cells, but lower potential for multi-lineage differentiation than BM-MSCs. TB-MSCs expressed higher levels of neural crest markers and lower levels of pericyte-specific markers. These neural crest-like properties of TB-MSCs were reflected by their propensity to differentiate into neuronal cells and proliferative response to nerve growth factors. Proteomics (LC–MS/MS) analysis revealed a distinct secretome profile of TB-MSCs compared to BM and adipose tissue-derived MSCs, exhibiting enrichments of factors for cell-extracellular matrix interaction and neurogenic signaling. However, TB-MSCs and BM-MSCs exhibited comparable suppressive effects on the allo-immune response and comparable stimulatory effects on hematopoietic stem cell self-renewal. In contrast, TB-MSCs stimulated growth and metastasis of breast cancer cells more than BM-MSCs. Altogether, our multi-donor characterization of TB-MSCs reveals distinct cell autonomous and paracrine properties, reflecting their unique developmental origin. These findings support using TB-MSCs as an alternative source of MSCs with distinct biological characteristics for optimal applications in cell therapy. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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18 pages, 4056 KiB

Open AccessArticle

Therapeutic Effects of Human Mesenchymal Stem Cells in a Mouse Model of Cerebellar Ataxia with Neuroinflammation

by Youngpyo Nam, Dongyeong Yoon, Jungwan Hong, Min Sung Kim, Tae Yong Lee, Kyung Suk Kim, Ho-Won Lee, Kyoungho Suk and Sang Ryong Kim

J. Clin. Med. 2020, 9(11), 3654; https://doi.org/10.3390/jcm9113654 - 13 Nov 2020

Cited by 5 | Viewed by 3290

Abstract

Cerebellar ataxias (CAs) are neurological diseases characterized by loss of muscle coordination that is a result of damage and inflammation to the cerebellum. Despite considerable efforts in basic and clinical research, most CAs are currently incurable. In this study, we evaluated the therapeutic potential of human mesenchymal stem cells (hMSCs) against CAs associated with neuroinflammation. We observed that hMSC treatment significantly inhibited the symptoms of ataxia in lipopolysaccharide (LPS)-induced inflammatory CA (ICA) mice, which were recently reported as a potential animal model of ICA, through the anti-inflammatory effect of hMSC-derived TNFα-stimulated gene-6 (TSG-6), the protection of Purkinje cells by inhibition of apoptosis, and the modulatory effect for microglial M2 polarization. Thus, our results suggest that hMSC treatment may be an effective therapeutic approach for preventing or improving ataxia symptoms. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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13 pages, 759 KiB

Open AccessArticle

Clinical Efficacy and Safety of Injection of Stromal Vascular Fraction Derived from Autologous Adipose Tissues in Systemic Sclerosis Patients with Hand Disability: A Proof-Of-Concept Trial

by Youngjae Park, Yoon Jae Lee, Jung Hee Koh, Jennifer Lee, Hong-Ki Min, Moon Young Kim, Ki Joo Kim, Su Jin Lee, Jong Won Rhie, Wan-Uk Kim, Sung-Hwan Park, Suk-Ho Moon and Seung-Ki Kwok

J. Clin. Med. 2020, 9(9), 3023; https://doi.org/10.3390/jcm9093023 - 19 Sep 2020

Cited by 19 | Viewed by 3410

Abstract

Background: Stromal vascular fraction (SVF) has recently emerged as a potential therapeutic modality, due to its multipotent cellular components in tissue regeneration. Systemic sclerosis (SSc) is a progressive autoimmune disease that results in hand disability by skin fibrosis and microangiopathies. We performed an open-label study to investigate the efficacy and safety of SVF injection in SSc patients (Clinical Trial number: NCT03060551). Methods: We gathered 20 SSc patients with hand disability, planning for a 24-week follow-up period. SVF was extracted from autologous adipose tissues, processed by the closed system kit, and injected into each finger of SSc patients. We observed various efficacy and safety profiles at each follow-up visit. Results: Among the 20 initially enrolled patients, eighteen received SVF injection, and were completely followed-up for the whole study period. Patients received 3.61 × 10⁶ mesenchymal stem cells into each finger on average. Skin fibrosis, hand edema, and quality of life were significantly improved, and 31.6% of active ulcers were healed at 24 weeks after injections. Semiquantitative results of nailfold capillary microscopy were ameliorated. There was no single serious adverse event related to the procedure. Conclusions: Injection of SVF derived from autologous adipose tissues is tolerable, and shows clinical efficacy in SSc patients. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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20 pages, 4153 KiB

Open AccessArticle

Xeno-Free Condition Enhances Therapeutic Functions of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis by Upregulated Indoleamine 2,3-Dioxygenase Activity

by Ji Yeon Kang, Mi-Kyung Oh, Hansol Joo, Hyun Sung Park, Dong-Hoon Chae, Jieun Kim, Hae-Ri Lee, Il-Hoan Oh and Kyung-Rok Yu

J. Clin. Med. 2020, 9(9), 2913; https://doi.org/10.3390/jcm9092913 - 10 Sep 2020

Cited by 19 | Viewed by 3696

Abstract

The therapeutic applications of mesenchymal stem cells (MSCs) have been actively explored due to their broad anti-inflammatory and immunomodulatory properties. However, the use of xenogeneic components, including fetal bovine serum (FBS), in the expansion media might pose a risk of xenoimmunization and zoonotic transmission to post-transplanted patients. Here, we extensively compared the physiological functions of human Wharton’s jelly-derived MSCs (WJ-MSCs) in a xeno-free medium (XF-MSCs) and a medium containing 10% FBS (10%-MSCs). Both groups showed similar proliferation potential; however, the 10%-MSCs showed prolonged expression of CD146, with higher colony-forming unit-fibroblast (CFU-F) ability than the XF-MSCs. The XF-MSCs showed enhanced adipogenic differentiation potential and sufficient hematopoietic stem cell (HSC) niche activity, with elevated niche-related markers including CXCL12. Furthermore, we demonstrated that the XF-MSCs had a significantly higher suppressive effect on human peripheral blood-derived T cell proliferation, Th1 and Th17 differentiation, as well as naïve macrophage polarization toward an M1 phenotype. Among the anti-inflammatory molecules, the production of indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase 2 (NOS2) was profoundly increased, whereas cyclooxygenase-2 (COX-2) was decreased in the XF-MSCs. Finally, the XF-MSCs had an enhanced therapeutic effect against mouse experimental colitis. These findings indicate that xeno-free culture conditions improved the immunomodulatory properties of WJ-MSCs and ex vivo-expanded XF-MSCs might be an effective strategy for preventing the progression of colitis. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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19 pages, 13781 KiB

Open AccessArticle

Therapeutic Efficacy of Human Embryonic Stem Cell-Derived Multipotent Stem/Stromal Cells in Diabetic Detrusor Underactivity: A Preclinical Study

by Jung Hyun Shin, Chae-Min Ryu, Hyein Ju, Hwan Yeul Yu, Sujin Song, Ki-Sung Hong, Hyung-Min Chung, Juhyun Park, Dong-Myung Shin and Myung-Soo Choo

J. Clin. Med. 2020, 9(9), 2853; https://doi.org/10.3390/jcm9092853 - 3 Sep 2020

Cited by 10 | Viewed by 2919

Abstract

Mesenchymal stem/stromal cell (MSC) therapy is a promising approach for treatment of as yet incurable detrusor underactivity (DUA), which is characterized by decreased detrusor contraction strength and/or duration, leading to prolonged bladder emptying. In the present study, we demonstrated the therapeutic potential of human embryonic stem cell (ESC)-derived multipotent MSCs (M-MSCs) in a diabetic rat model of DUA. Diabetes mellitus (DM) was induced by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) into 8-week-old female Sprague-Dawley rats. Three weeks later, various doses of M-MSCs (0.25, 0.5, and 1 × 10⁶ cells) or an equivalent volume of PBS were injected into the outer layer of the bladder. Awake cystometry, organ bath, histological, and gene expression analyses were evaluated 1 week (short-term) or 2 and 4 weeks (long-term) after M-MSC transplantation. STZ-induced diabetic rats developed DUA, including phenotypes with significantly longer micturition intervals, increased residual urine amounts and bladder capacity, decreased micturition pressure on awake cystometry, and contractile responses to various stimuli in organ bath studies. Muscle degeneration, mast cell infiltration, fibrosis, and apoptosis were present in the bladders of DM animals. A single local transplantation of M-MSCs ameliorated DUA bladder pathology, including functional changes and histological evaluation, and caused few adverse outcomes. Immunostaining and gene expression analysis revealed that the transplanted M-MSCs supported myogenic restoration primarily by engrafting into bladder tissue via pericytes, and subsequently exerting paracrine effects to prevent apoptotic cell death in bladder tissue. The therapeutic efficacy of M-MSCs was superior to that of human umbilical cord-derived MSCs at the early time point (1 week). However, the difference in efficacy between M-MSCs and human umbilical cord-derived MSCs was statistically insignificant at the later time points (2 and 4 weeks). Collectively, the present study provides the first evidence for improved therapeutic efficacy of a human ESC derivative in a preclinical model of DM-associated DUA. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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Review

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17 pages, 740 KiB

Open AccessReview

The Use of Adipose-Derived Stem Cells (ADSCs) and Stromal Vascular Fraction (SVF) in Skin Scar Treatment—A Systematic Review of Clinical Studies

by Albert Stachura, Wiktor Paskal, Weronika Pawlik, Maciej J. Mazurek and Janusz Jaworowski

J. Clin. Med. 2021, 10(16), 3637; https://doi.org/10.3390/jcm10163637 - 17 Aug 2021

Cited by 22 | Viewed by 5398

Abstract

In recent years, lipofilling became a popular scar treatment method. Its beneficial outcomes have been partly attributed to the regenerative capacity of adipose-derived stem cells (ADSCs), suspended in an extracellular matrix—the stromal vascular fraction (SVF). The aim of this review was to verify if existing data support the clinical use of ADSC-related interventions in scar treatment. A systematic search of the literature was performed in July 2020 in five databases (Medline, Cochrane, Web of Science, Scopus and Embase). Articles written in English, except for reviews, letters and editorials, were identified and screened for eligibility. We looked for reports of any outcomes in scars treated with ADSCs or SVF. Data from selected articles were extracted and the quality of each study was assessed. Five hundred and fourteen studies were identified in the primary search, of which nineteen were eventually included in the systematic review. Extracted data pointed to beneficial microscopic, functional and aesthetic outcomes in a total of 665 patients. Six studies included comparative interventions—platelet-rich plasma or CO₂ fractional laser. Collected data give low-to-average quality evidence for beneficial effects of ADSC-related interventions in scar treatment. Some studies suggest that these interventions are noninferior to PRP or fractional CO₂ laser. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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51 pages, 18506 KiB

Open AccessReview

Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review

by Manuel Sanchez-Diaz, Maria I. Quiñones-Vico, Raquel Sanabria de la Torre, Trinidad Montero-Vílchez, Alvaro Sierra-Sánchez, Alejandro Molina-Leyva and Salvador Arias-Santiago

J. Clin. Med. 2021, 10(13), 2925; https://doi.org/10.3390/jcm10132925 - 29 Jun 2021

Cited by 61 | Viewed by 5409

Abstract

Mesenchymal Stromal Cells (MSCs) are of great interest in cellular therapy. Different routes of administration of MSCs have been described both in pre-clinical and clinical reports. Knowledge about the fate of the administered cells is critical for developing MSC-based therapies. The aim of this review is to describe how MSCs are distributed after injection, using different administration routes in animal models and humans. A literature search was performed in order to consider how MSCs distribute after intravenous, intraarterial, intramuscular, intraarticular and intralesional injection into both animal models and humans. Studies addressing the biodistribution of MSCs in “in vivo” animal models and humans were included. After the search, 109 articles were included in the review. Intravenous administration of MSCs is widely used; it leads to an initial accumulation of cells in the lungs with later redistribution to the liver, spleen and kidneys. Intraarterial infusion bypasses the lungs, so MSCs distribute widely throughout the rest of the body. Intramuscular, intraarticular and intradermal administration lack systemic biodistribution. Injection into various specific organs is also described. Biodistribution of MSCs in animal models and humans appears to be similar and depends on the route of administration. More studies with standardized protocols of MSC administration could be useful in order to make results homogeneous and more comparable. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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18 pages, 943 KiB

Open AccessReview

Therapeutic Features and Updated Clinical Trials of Mesenchymal Stem Cell (MSC)-Derived Exosomes

by Byung-Chul Lee, Insung Kang and Kyung-Rok Yu

J. Clin. Med. 2021, 10(4), 711; https://doi.org/10.3390/jcm10040711 - 11 Feb 2021

Cited by 112 | Viewed by 14035

Abstract

Identification of the immunomodulatory and regenerative properties of mesenchymal stem cells (MSCs) have made them an attractive alternative therapeutic option for diseases with no effective treatment options. Numerous clinical trials have followed; however, issues such as infusional toxicity and cellular rejection have been reported. To address these problems associated with cell-based therapy, MSC exosome therapy was developed and has shown promising clinical outcomes. MSC exosomes are nanosized vesicles secreted from MSCs and represent a non-cellular therapeutic agent. MSC exosomes retain therapeutic features of the cells from which they originated including genetic material, lipids, and proteins. Similar to MSCs, exosomes can induce cell differentiation, immunoregulation, angiogenesis, and tumor suppression. MSC exosomes have therefore been employed in several experimental models and clinical studies. Here, we review the therapeutic potential of MSC-derived exosomes and summarize currently ongoing clinical trials according to disease type. In addition, we propose several functional enhancement strategies for the effective clinical application of MSC exosome therapy. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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27 pages, 1592 KiB

Open AccessReview

Exosome: A New Player in Translational Nanomedicine

by Houssam Aheget, María Tristán-Manzano, Loubna Mazini, Marina Cortijo-Gutierrez, Pablo Galindo-Moreno, Concha Herrera, Francisco Martin, Juan Antonio Marchal and Karim Benabdellah

J. Clin. Med. 2020, 9(8), 2380; https://doi.org/10.3390/jcm9082380 - 26 Jul 2020

Cited by 56 | Viewed by 10074

Abstract

Summary: Exosomes are extracellular vesicles released by the vast majority of cell types both in vivo and ex vivo, upon the fusion of multivesicular bodies (MVBs) with the cellular plasma membrane. Two main functions have been attributed to exosomes: their capacity to transport proteins, lipids and nucleic acids between cells and organs, as well as their potential to act as natural intercellular communicators in normal biological processes and in pathologies. From a clinical perspective, the majority of applications use exosomes as biomarkers of disease. A new approach uses exosomes as biologically active carriers to provide a platform for the enhanced delivery of cargo in vivo. One of the major limitations in developing exosome-based therapies is the difficulty of producing sufficient amounts of safe and efficient exosomes. The identification of potential proteins involved in exosome biogenesis is expected to directly cause a deliberate increase in exosome production. In this review, we summarize the current state of knowledge regarding exosomes, with particular emphasis on their structural features, biosynthesis pathways, production techniques and potential clinical applications. Full article

(This article belongs to the Special Issue Therapies Based on Mesenchymal Stem Cells (MSCs) and MSC-Derived Exosomes)

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