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

Abstract

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.

Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs

“…Each process is highly regulated and EVs are most probably involved in the cross-talk between the cells. This can be assumed from literature, demonstrating the positive impact of MSC EVs on fracture healing and bone regeneration ( Tan et al, 2020 ; Zhang et al, 2020 ). The study of Brady et al (2018) confirms our suggestion, it reported that shared as well as unique proteins were identified in serum-derived exosomes of dogs with a traumatic bone fracture in comparison to normal dogs.…”

BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

“…Recently, extracellular vesicles (EVs), such as exosomes and microvesicles, have been attracting a strong research interest for use as natural drug delivery systems ( Chen et al, 2018 ; Tang and Wang, 2020 ). Mesenchymal stem cell (MSC)-derived exosomes have been reported to be involved in multiple physiology and pathology activities including osteogenesis, bone regeneration, osteoarthritis, cardiomyoblast hypoxia–reperfusion, cognitive impairment, inflammation, stroke, sepsis, and tumorigenesis ( Zheng et al, 2018 ; Huang et al, 2020 ; Jin et al, 2020 ; Nakano et al, 2020 ; Tan et al, 2020 ; Venkat et al, 2020 ; Xu et al, 2020 ; Zou et al, 2020 ). Jia et al (2020) report that exosomes secreted by young MSCs promote osteogenesis and bone formation in older rats.…”

Exosomes Derived from Cyclic Mechanical Stretch-exposed Bone Marrow Mesenchymal Stem Cells Inhibit RANKL-induced Osteoclastogenesis through the NF-κB Signaling Pathway

“…Increasing evidence has shown the therapeutic potential of exosomes in treating various bone diseases [30,31]. The bone mineral density of bovine colostrum exosome-fed glucocorticoid-induced osteoporosis mice was signi cantly improved compared with that of control mice without exosome treatment [32].…”