Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tendon and Ligament Repair—A Systematic Review of In Vivo Studies

Tendon and ligament injury poses an increasingly large burden to society. This systematic review explores whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can facilitate tendon/ligament repair in vivo. On 26 May 2021, a systematic search was performed on PubMed, Web of Science, Cochrane Library, Embase, to identify all studies that utilised MSC-EVs for tendon/ligament healing. Studies administering EVs isolated from human or animal-derived MSCs into in vivo models of tendon/ligament injury were included. In vitro, ex vivo, and in silico studies were excluded, and studies without a control group were excluded. Out of 383 studies identified, 11 met the inclusion criteria. Data on isolation, the characterisation of MSCs and EVs, and the in vivo findings in in vivo models were extracted. All included studies reported better tendon/ligament repair following MSC-EV treatment, but not all found improvements in every parameter measured. Biomechanics, an important index for tendon/ligament repair, was reported by only eight studies, from which evidence linking biomechanical alterations to functional improvement was weak. Nevertheless, the studies in this review showcased the safety and efficacy of MSC-EV therapy for tendon/ligament healing, by attenuating the initial inflammatory response and accelerating tendon matrix regeneration, providing a basis for potential clinical use in tendon/ligament repair.

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Bone Regeneration Improves with Mesenchymal Stem Cell Derived Extracellular Vesicles (EVs) Combined with Scaffolds: A Systematic Review

Biology ◽

10.3390/biology10070579 ◽

2021 ◽

Vol 10 (7) ◽

pp. 579

Author(s):

Federica Re ◽

Elena Gabusi ◽

Cristina Manferdini ◽

Domenico Russo ◽

Gina Lisignoli

Keyword(s):

Systematic Review ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Bone Regeneration ◽

Extracellular Vesicles ◽

Bone Mineralization ◽

In Vivo Studies ◽

Positive Effects

Scaffolds associated with mesenchymal stem cell (MSC) derivatives, such as extracellular vesicles (EVs), represent interesting carriers for bone regeneration. This systematic review aims to analyze in vitro and in vivo studies that report the effects of EVs combined with scaffolds in bone regeneration. A methodical review of the literature was performed from PubMed and Embase from 2012 to 2020. Sixteen papers were analyzed; of these, one study was in vitro, eleven were in vivo, and four were both in vitro and in vivo studies. This analysis shows a growing interest in this upcoming field, with overall positive results. In vitro results were demonstrated as both an effect on bone mineralization and proangiogenic ability. The interesting in vitro outcomes were confirmed in vivo. Particularly, these studies showed positive effects on bone regeneration and mineralization, activation of the pathway for bone regeneration, induction of vascularization, and modulation of inflammation. However, several aspects remain to be elucidated, such as the concentration of EVs to use in clinic for bone-related applications and the definition of the real advantages.

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The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.00580 ◽

2020 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Kendrick To ◽

Karl Romain ◽

Christopher Mak ◽

Achi Kamaraj ◽

Frances Henson ◽

...

Keyword(s):

Systematic Review ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Cartilage Damage ◽

Human Mesenchymal Stem Cell ◽

In Vivo Studies

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Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

Cells ◽

10.3390/cells10040730 ◽

2021 ◽

Vol 10 (4) ◽

pp. 730

Author(s):

Biji Mathew ◽

Leianne A. Torres ◽

Lorea Gamboa Gamboa Acha ◽

Sophie Tran ◽

Alice Liu ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Time Course ◽

Ganglion Cells ◽

Ex Vivo ◽

Dependent Manner ◽

Paracrine Effects

Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy and glaucoma. This approach has significant limitations, including few cells integrated, aberrant growth, and surgical complications. Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes and microvesicles, are an emerging alternative, promoting immunomodulation, repair, and regeneration by mediating MSC’s paracrine effects. For the clinical translation of EV therapy, it is important to determine the cellular destination and time course of EV uptake in the retina following administration. Here, we tested the cellular fate of EVs using in vivo rat retinas, ex vivo retinal explant, and primary retinal cells. Intravitreally administered fluorescent EVs were rapidly cleared from the vitreous. Retinal ganglion cells (RGCs) had maximal EV fluorescence at 14 days post administration, and microglia at 7 days. Both in vivo and in the explant model, most EVs were no deeper than the inner nuclear layer. Retinal astrocytes, microglia, and mixed neurons in vitro endocytosed EVs in a dose-dependent manner. Thus, our results indicate that intravitreal EVs are suited for the treatment of retinal diseases affecting the inner retina. Modification of the EV surface should be considered for maintaining EVs in the vitreous for prolonged delivery.

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Mesenchymal Stem Cell Therapy for Acetaminophen-Related Liver Injury: A Systematic Review and Meta-Analysis of Experimental Studies in Vivo

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666211007092055 ◽

2021 ◽

Vol 16 ◽

Author(s):

Li Wang ◽

Yiwen Zhang ◽

Jiajun Zhong ◽

Yuan Zhang ◽

Shuisheng Zhou ◽

...

Keyword(s):

Systematic Review ◽

Stem Cell ◽

Liver Injury ◽

Mesenchymal Stem Cell ◽

Small Sample Size ◽

Meta Analysis ◽

Experimental Studies ◽

Small Sample ◽

Control Group

Objective: The efficacy of mesenchymal stem cell (MSC) therapy in acetaminophen-induced liver injury has been investigated in animal experiments, but individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis of preclinical studies to explore the potential of using MSCs in acetaminophen-induced liver injury. Methods: Eight databases were searched for studies reporting the effects of MSCs on acetaminophen hepatoxicity. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used. SYRCLE’s risk of bias tool for animal studies was applied to assess the methodological quality. A meta-analysis was performed by using RevMan 5.4 and STATA/SE 16.0 software. Results: Eleven studies involving 159 animals were included according to PRISMA statement guidelines. Significant associations were found for MSCs with the levels of alanine transaminase (ALT) (standardized mean difference (SMD) − 2.58, p < 0.0001), aspartate aminotransferase (AST) (SMD − 1.75, p = 0.001), glutathione (GSH) (SMD 3.7, p < 0.0001), superoxide dismutase (SOD) (SMD 1.86, p = 0.022), interleukin 10 (IL-10) (SMD 5.14, p = 0.0002) and tumor necrosis factor-α (TNF-α) (SMD − 4.48, p = 0.011) compared with those in the control group. The subgroup analysis showed that the tissue source of MSCs significantly affected the therapeutic efficacy (p < 0.05). Conclusion: Our meta-analysis results demonstrate that MSCs could be a potential treatment for acetaminophen-related liver injury.

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Enhancement of Chondrogenesis in Hypoxic Precondition Culture: A Systematic Review

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.5850 ◽

2021 ◽

Vol 9 (F) ◽

pp. 492-504

Author(s):

Sholahuddin Rhatomy ◽

Riky Setyawan ◽

Michael Aaron Romulo

Keyword(s):

Systematic Review ◽

Stem Cells ◽

Stem Cell ◽

Meta Analysis ◽

Cochrane Library ◽

Oxygen Level ◽

Hypoxic Precondition ◽

Online Library

BACKGROUND: Cartilage tear has begun to be treated with stem cells. However, stem cell oxygen level culture has not been evaluated for the best environment to enhance chondrogenesis. AIM: The purpose of this review is to focus on the hypoxic oxygen level of stem cells culture as a treatment for cartilage tear. METHODS: A literature search was systemically conducted on PubMed (MEDLINE), OVID, EMBASE, the Cochrane Library, Scopus, Web of Science, Science Direct, Wiley Online Library, Google Scholar, and bibliography of selected articles with the terms (“culture”) AND (“stem cell” OR “mesenchymal stem cell” OR “MSC”) AND (“hypoxic” OR “hypoxia”) AND (“cartilage” OR “chondro*”) as the main keywords. A total of 438 articles were reviewed. Thirty-six articles were considered relevant for this systematic review. RESULTS: The result of this review supports stimulation effects of hypoxic oxygen level stem cell culture in chondrogenesis process. Most studies used 5% oxygen concentration for culture, both of in vivo and in vitro studies. Due to the heterogeneity nature of the included studies, meta-analysis was unable to be conducted. CONCLUSION: Hypoxia state seems to play an important role in chondrocytes proliferation, differentiation, and matrix production.

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Mesenchymal Stem Cell Exosomes in the Treatment of Myocardial Infarction: a Systematic Review of Preclinical In Vivo Studies

Journal of Cardiovascular Translational Research ◽

10.1007/s12265-021-10168-y ◽

2021 ◽

Author(s):

Hui Meng ◽

Weiting Cheng ◽

Lei Wang ◽

Shiqi Chen ◽

Yu Teng ◽

...

Keyword(s):

Myocardial Infarction ◽

Systematic Review ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

In Vivo Studies

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The Comparative Effects of Mesenchymal Stem Cell Transplantation Therapy for Spinal Cord Injury in Humans and Animal Models: A Systematic Review and Meta-Analysis

Biology ◽

10.3390/biology10030230 ◽

2021 ◽

Vol 10 (3) ◽

pp. 230

Author(s):

Louis D. V. Johnson ◽

Mark R. Pickard ◽

William E. B. Johnson

Keyword(s):

Systematic Review ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Animal Models ◽

Mesenchymal Stem Cell ◽

Meta Analysis ◽

Sensory Function ◽

Cochrane Library ◽

Cord Injury

Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. This systematic review and meta-analysis has examined the effects of MSC transplants in human and animal studies. Following searches of PubMed, Clinical Trials and the Cochrane Library, published papers were screened, and data were extracted and analysed. MSC transplantation was associated with significantly improved motor and sensory function in humans, and significantly increased locomotor function in animals. However, there are discrepancies between the studies of human participants and animal models, including timing of MSC transplant post-injury and source of MSCs. Additionally, difficulty in the comparison of functional outcome measures across species limits the predictive nature of the animal research. These findings have been summarised, and recommendations for further research are discussed to better enable the translation of animal models to MSC-based human clinical therapy.

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