Mesenchymal Stem Cell Exosomes for Cartilage Regeneration: A Systematic Review of Preclinical <i>In Vivo</i> Studies

Tan, Si Heng Sharon; Tjio, Calvin Kai En; Wong, Joshua; Wong, Kainam Thomas; Chew, Jacob Ren Jie; Hui, James Hoi Po; Toh, Wei Seong

doi:10.1089/ten.teb.2019.0326

Cited by 60 publications

(60 citation statements)

References 32 publications

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“…As the main component of MSC secretome, extracellular vesicles after entering the cells regulate gene transcription and the function of recipient cells [ 218 , 219 , 220 ]. A recent study analyzed 13 preclinical studies that used MSC exosomes for cartilage repair and showed that in most studies, exosome treated animals shown increased cellular proliferation, augmented matrix deposition, and better histological scores [ 221 ]. Some authors argue that, in comparison with MSCs treatment, exosome-based therapy is more sustainable, reproducible and safe, primarily because of reduced toxicity and immunogenicity issues [ 222 , 223 ].…”

Section: State-of-the-art Non-operative Therapeutic Considerationmentioning

confidence: 99%

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Primorac

Molnar

Rod

et al. 2020

Genes

256

176

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Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients. In the following review, we summarized all of the latest and most important research in basic sciences, pathogenesis, and non-operative treatment.

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Section: State-of-the-art Non-operative Therapeutic Considerationmentioning

confidence: 99%

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Primorac

Molnar

Rod

et al. 2020

Genes

256

176

View full text Add to dashboard Cite

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“…In bone regeneration, several clinical studies have demonstrated MSCs to be safe and efficacious for the treatment of bone defects and diseases such as osteonecrosis [ [18] , [19] , [20] , [21] , [22] ]. Despite their therapeutic effects, cellular MSC therapies incur significant costs and challenges as they require stringently monitored manufacturing, handling, and storage to ensure optimal viability and potency of cells needed for transplantation [ 23 ]. Although the use of MSCs for tissue repair such as bone regeneration was first predicated on the hypothesis that these cells could differentiate into osteoblasts to replace the damaged tissue, it is now apparent that MSCs secrete factors involved in cellular processes such as chemotaxis, angiogenesis, and osteogenesis to promote overall bone regeneration [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Increasingly, MSC exosomes have replicated the wide-ranging therapeutic efficacies of MSCs in several injury and disease indications such as myocardial ischemia reperfusion injury [ 29 ], drug-induced liver injury [ 30 ], retinal laser injury [ 31 ], pulmonary hypertension [ 32 ], and graft-versus-host-disease [ 33 , 34 ]. MSC exosomes were also reported to be efficacious in enhancing skeletal muscle regeneration [ 35 , 36 ] and more recently cartilage [ 23 , [37] , [38] , [39] , [40] ] and bone regeneration [ [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] ].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell exosomes in bone regenerative strategies—a systematic review of preclinical studies

Tan

Wong

Sim

et al. 2020

Materials Today Bio

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The ability of bone for regeneration has long been recognized. However, once beyond a critical size, spontaneous regeneration of bone is limited. Several studies have focused on enhancing bone regeneration by applying mesenchymal stromal/stem cells (MSCs) in the treatment strategies. Despite the therapeutic efficacy of MSCs in bone regeneration, cell-based therapies are impeded by several challenges in maintaining the optimal cell potency and viability during expansion, storage, and final delivery to patients. Recently, there has been a paradigm shift in therapeutic mechanism of MSCs in tissue repair from one based on cellular differentiation and replacement to one based on secretion and paracrine signaling. Among the broad spectrum of trophic factors, extracellular vesicles particularly the exosomes have been reported to be therapeutically efficacious in several injury/disease indications, including bone defects and diseases. The current systematic review aims to summarize the results of the existing animal studies which were conducted to evaluate the therapeutic efficacy of MSC exosomes for bone regeneration. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, the PubMed and The Cochrane Library database were searched for relevant controlled preclinical animal studies. A total of 23 studies were identified, with the total sample size being 690 rats or mice and 38 rabbits. Generally, MSC exosomes were found to be efficacious for bone regeneration in animal models of bone defects and diseases such as osteonecrosis and osteoporosis. In these studies, MSC exosomes promoted new bone formation with supporting vasculature and displayed improved morphological, biomechanical, and histological outcomes, coupled with positive effects on cell survival, proliferation, and migration, osteogenesis, and angiogenesis. Unclear-to-low risk in bias and incomplete reporting in the primary studies highlighted the need for standardization in outcome measurements and reporting. Further studies in large animal models to establish the safety and efficacy would provide useful information on guiding the design of clinical trials.

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“…In recent years, studies have shown that the role of stem cells in tissue repair is accomplished through the activation of peripheral receptor cells by exosomes secreted by their paracrine mechanism (Tan et al, 2020;Wang et al, 2020;Zhang B. et al, 2020). The exosome molecule is 50-150 nm in diameter, and it mainly contains cytokines, growth factors and other proteins, lipids, coding, or non-coding RNAs similar to the cells of origin, and participates in cell communication, cell migration, vascular regeneration and other processes, which plays an important role in the regulation of cell physiological functions (Li et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

BMSC-Exosomes Carry Mutant HIF-1α for Improving Angiogenesis and Osteogenesis in Critical-Sized Calvarial Defects

Ying

Wang

et al. 2020

Front. Bioeng. Biotechnol.

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Repair and reconstruction of critical-sized bone defects has always been a difficult task in orthopedics. Hypoxia inducible factor-1α (HIF-1α) plays an important role in bone defect repair, it has the dual function of promoting osteogenesis and vascular regeneration, but it is quickly degraded by the body under normoxic conditions. Previously we prepared mutant HIF-1α, which has been shown to efficiently maintain cellular expression under normoxic conditions. In this study, we evaluated for the first time the role of exosomes of rat bone marrow mesenchymal stem cell carry mutant HIF-1α (BMSC-Exos-HIF1α) in repairing critical-sized bone defects. Evaluation of the effects of BMSC-Exos-HIF1α on bone marrow mesenchymal stem cells (BMSCs) proliferation and osteogenic differentiation by cell proliferation assay, alkaline phosphatase activity assay, alizarin red staining, real-time quantitative polymerase chain reaction. BMSC-Exos-HIF1α was loaded onto the β-TCP stent implanted in the bone defect area using a rat cranial critical-sized bone defect model, and new bone formation and neovascularization were detected in vivo by micro-CT, fluorescence labeling analysis, Microfil perfusion, histology and immunohistochemical analysis. In vitro results showed that BMSC-Exos-HIF1α stimulated the proliferation of BMSCs and upregulated the expression level of bone-related genes, which was superior to bone marrow MSC exosomes (BMSC-Exos). In vivo results showed that BMSC-Exos-HIF1α combined with β-TCP scaffold promoted new bone regeneration and neovascularization in the bone defect area, and the effect was better than that of BMSC-Exos combined with β-TCP scaffold. In this study, the results showed that BMSC-Exos-HIF1α stimulated the proliferation and osteogenic differentiation of BMSCs and that BMSC-Exos-HIF1α combined with β-TCP scaffolds could repair critical-sized bone defects by promoting new bone regeneration and neovascularization.

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Mesenchymal Stem Cell Exosomes for Cartilage Regeneration: A Systematic Review of Preclinical In Vivo Studies

Cited by 60 publications

References 32 publications

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations

Mesenchymal stem cell exosomes in bone regenerative strategies—a systematic review of preclinical studies

BMSC-Exosomes Carry Mutant HIF-1α for Improving Angiogenesis and Osteogenesis in Critical-Sized Calvarial Defects

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