The Role of Paracrine Regulation of Mesenchymal Stem Cells in the Crosstalk With Macrophages in Musculoskeletal Diseases: A Systematic Review

Abstract

The phenotypic change of macrophages (Mφs) plays a crucial role in the musculoskeletal homeostasis and repair process. Although mesenchymal stem cells (MSCs) have been shown as a novel approach in tissue regeneration, the therapeutic potential of MSCs mediated by the interaction between MSC-derived paracrine mediators and Mφs remains elusive. This review focused on the elucidation of paracrine crosstalk between MSCs and Mφs during musculoskeletal diseases and injury. The search method was based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane Guidelines. The search strategies included MeSH terms and other related terms of MSC-derived mediators and Mφs. Ten studies formed the basis of this review. The current finding suggested that MSC administration promoted proliferation and activation of CD163⁺ or CD206⁺ M2 Mφs in parallel with reduction of proinflammatory cytokines and increase in anti-inflammatory cytokines. During such period, Mφs also induced MSCs into a motile and active phenotype via the influence of proinflammatory cytokines. Such crosstalk between Mφs and MSCs further strengthens the effect of paracrine mediators from MSCs to regulate Mφs phenotypic alteration. In conclusion, MSCs in musculoskeletal system, mediated by the interaction between MSC paracrine and Mφs, have therapeutic potential in musculoskeletal diseases.

Keywords: exosomes; extracellular vesicles (EVs); macrophages; mesenchymal stem cells (MeSH ID D059630); musculoskeletal.

Figure 1

Flowchart presenting the results of the literature search and the strategy used to select studies that relate to the crosstalk between MSCs and Mφs of musculoskeletal diseases. Study selection process. The search revealed 433 records. A total of 93 overlaps were removed between the databases. The remaining 340 records were screened by title and abstract, and 322 records were excluded. The remaining 18 studies were examined using their full texts, and finally ten eligible studies were identified.

Figure 2

Representative graph of the included studies presented in the articles reviewed. (A) Publication year of included studies (range from 2015 to 2020). (B) Target disease of included studies (include bone fracture, OA, muscle damage, tendon injury). (C) Experimental model of included studies (including mice model, rat model, in vitro experiment only). (D) Paracrine factors (including extracellular vesicle, exosomes, CM). (E) Cell source of included studies (including human, C57Bl/6 mice, other genotype mice, SD rat, cell line).

Figure 3

Schematic illustration of MSC-derived exosome-guided macrophage reprogramming. MSC-derived exosomes can induce a conversion of M1 to M2 Mφs and accelerate musculoskeletal tissue healing. Mφs could be activated by inflammatory chemokines and then to produce proinflammatory factors. This creates a feedback loop whereby proinflammatory cytokines produced by Mφs stimulate MSC to produce immune modulators, such as exosomes or EVs. Therefore, the formation of exosomes begins with membrane invagination in the form of endosomes, leading to the development of the early endosomes. Upon maturation, the endosomes become multivesicular endosomes, which release their contents in the form of exosomes.