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.

Keywords: Bone; Exosomes; Extracellular vesicles; Mesenchymal stem cells; Regeneration; Systematic review.

Graphical abstract

Fig. 1

PRISMA flow diagram of the review and selection of studies. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

Fig. 2

Key factors and outcomes identified in preclinical studies of MSC exosomes for bone regeneration. MSC, mesenchymal stem cell; HA, hyaluronic acid; HAp, hydroxyapatite; β-TCP, beta-tricalcium phosphate; PLGA, poly-lactic-co-glycolic acid.

Fig. 3

Bar chart showing the number of the published studies included in the systematic review sorted by the year of publication.

Fig. 4

MSC exosomes alleviate the pathological processes in bone injury/disease to promote regeneration through a multifaceted mechanism of enhancing cell survival, proliferation and migration, and promoting osteogenesis and angiogenesis. MSC, mesenchymal stem cell.