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Review
. 2021 Jan;128(1):18-36.
doi: 10.1111/bcpt.13478. Epub 2020 Sep 22.

Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration

Xiaoqin Wang  1 , Peter Thomsen  1
Affiliations
Review

Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration

Xiaoqin Wang et al. Basic Clin Pharmacol Toxicol. 2021 Jan.

Abstract

Mesenchymal stem cells (MSCs) and MSC-derived small extracellular vesicles (sEVs) are promising candidates for cell-based and cell-free regenerative medicine, respectively. By virtue of their multiple lineage differentiation capacity, MSCs have been implicated as an ideal tool for bone and cartilage regeneration. However, later observations attributed such regenerative effects to MSC-secreted paracrine factors. Exosomes, endosomal originated sEVs carrying lipid, protein and nucleic acid cargoes, were identified as components of the MSC secretome and propagated the key regenerative and immunoregulatory characteristics of parental MSCs. Here, exosome biogenesis, the molecular composition of exosomes, sEV-cell interactions and the effects on key bone homeostasis cells are reviewed. MSC-derived sEVs show to promote neovascularization and bone and cartilage regeneration in preclinical disease models. The mechanisms include the transfer of molecules, including microRNAs, mRNAs and proteins, to other key cells. MSC-derived sEVs are interesting candidates as biopharmaceuticals for drug delivery and for the engineering of biologically functionalized materials. Although major exploratory efforts have been made for therapeutic development, the secretion, distribution and biological effects of MSC-derived sEVs in bone and cartilage regeneration are not fully understood. Moreover, techniques for high-yield production, purity and storage need to be optimized before effective and safe MSC-derived sEVs therapies are realized.

Keywords: Bone regeneration; Cell-cell communication; Exosomes; Mesenchymal stem cells; small extracellular vesicles.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Multiple cellular and molecular interactions during bone regeneration. Some of the representative cellular interactions and responsible molecules are illustrated in the figure. (1) MSCs—OB/osteocytes: MSCs commit to osteoblasts and terminally differentiate to osteocytes. The secretion of SDF‐1α, TGFβ and BMPs promotes the migration and differentiation of osteoblastic progenitor cells. (2) MSCs—Mo/Mϕ: MSCs regulate migration, proliferation, differentiation and polarization of monocytes/macrophages via secretion of MCP‐1, M‐CSF, PGE2 and IDO. (3) MSCs/OB—Mo/OC: MSCs/osteoblasts interact with the osteoclastic li—neage via secretion of M‐CSF, RANKL and OPG, which regulate the proliferation, differentiation and activation of osteoclasts. (4) Mo/MΦ—OC: Macrophages differentially influence the activity of osteoclasts via secretion of pro‐ or anti‐inflammatory cytokines, depending on the Mϕ phenotypes. (5) MSCs—EC: MSC‐secreted VEGF and AGN promote angiogenesis via increased proliferation, migration and tube formation of endothelial cells. OB, osteoblast; OC, osteoclast; Mo, monocyte; Mϕ, macrophage; M1 Mϕ, proinflammatory Mϕ; M2 Mϕ, anti‐inflammatory Mϕ; EC, endothelial cell; SDF‐1α, stromal cell‐derived factor 1α; TGFβ, transforming growth factor β; BMPs, bone morphogenetic proteins; M‐CSF, macrophage colony‐stimulating factor; RANK, receptor activator of nuclear factor‐κB; RANKL, RANK ligand; OPG, osteoprotegerin; MCP‐1, monocyte chemoattractant protein‐1; PGE2, prostaglandin E2; IDO, indoleamine 2,3‐dioxygenase; IL‐1β, interleukin 1β; IL‐10, interleukin 10; TNFα, tumour necrosis factor α; VEGF, vascular endothelial growth factor; AGN, angiostatin. The figure is adapted from Elgali 3 (Figure 2) (with permission from Dr Cecilia Graneli, Sweden).
Figure 2
Figure 2
Biogenesis of exosomes. The biogenesis and secretion of exosomes is regulated by both ESCRT‐dependent and ESCRT‐independent machinery. ESCRT, endosomal sorting complex required for transport; ARF6, ADP ribosylation factor 6; SMase, sphingomyelinase; Tsg101, tumour susceptibility gene 101 protein; VPS4, vacuolar protein sorting‐associated protein 4; ILV, intraluminal vesicle; MVB, multivesicular body; PM, plasma membrane. From Wang 39 ; reprinted with permission.
Figure 3
Figure 3
Molecular composition of exosomes. Exosomes have a molecular composition that includes numerous lipids, proteins and nucleic acids. The figure is adapted and republished with permission of Annual Review of Cell and Developmental Biology, from Biogenesis, secretion and intercellular interactions of exosomes and other extracellular vesicles, Colombo Marina; Raposo Graça; Théry Clotilde, Vol 30, 2014 20 ; permission conveyed through Copyright Clearance Center, Inc
Figure 4
Figure 4
Effects of MSC‐derived sEVs on multiple cell types involved in bone and cartilage regeneration. HUVEC, human umbilical vein endothelial cell; Mo, monocyte; M ϕ, macrophage; OC, osteoclast; MSC, mesenchymal stem cell; OB, osteoblast; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; ROS, reactive oxygen species; H/SD, hypoxia and serum deprivation; RANKL, receptor activator of nuclear factor‐κB ligand; OPG, osteoprotegerin; IL6, interleukin 6; IL10, interleukin 10; TLR, Toll‐like receptor; M1/M2, pro‐ and anti‐inflammatory macrophage phenotypes; IL‐1β, interleukin 1; SA‐β‐Gal, senescence‐associated β‐galactosidase; γH2AX, phosphorylated H2A histone family member X; COX2, cyclooxygenase‐2; iNOS, inducible nitric oxide synthase; NO, nitric oxide; NFκB, nuclear factor‐κB.
Figure 5
Figure 5
Functionalized titanium implant surface by immobilization of exosomes. The exosome‐immobilized titanium surface may offer combined advantages to modify the surface nanotopography and provide biosignals on the surface by the bioactive molecules presented on the immobilized exosomes. im‐Exo, immobilized exosomes. From Wang 128 ; reprinted with permission.
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