Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine

Table 1 The main proteins and miRNAs having an effect on bone homeostasis are shown in the table as well as their putative function in this process and the corresponding references where this activity is described

MSC-EVs CARGO
Proteins	Bone healing functions	Ref.
MCP-1	Induces angiogenesis and MSC recruitment to injury site	[107]
MCP-3	Promotes cell proliferation and MSC recruitment to injury site	[107]
SDF-1 α	Recruits osteoprogenitor cells to wound area	[100]
IL-6	Induces endothelial/endothelial progenitor cell proliferation angiogenesis and osteogenesis	[107]
FGF-2	Fosters proliferation, differentiation and migration of vascular cells, chondrocytes and osteoblasts	[103,110,111]
PDGF-B	Promotes mesenchymal proliferation, potentiates cartilage and intramembranous bone formation and stimulates angiogenic pathways	[100,103,114]
VEGF	Promotes revascularization, regulation of vascular endothelial cell migration, proliferation, and capillary production, and improves the cellular activity of osteoblasts	[99]
ANGPTL2	Potentiates sprouting in endothelial cells	[114]
Fibronectin	Collaborates in cell movement and migration and provides provisional fibers in cartilaginous matrices	[103]
IGF-I	Induces collagen synthesis, reduces collagen degradation, promotes clonal expansion of chondrocytes and proliferation of preosteoblastic cells, and regulates migration of osteoblasts and MSCs	[103]
TGF-β1	Chemoattraction of macrophages, enhances migration, proliferation and differentiation of osteoprogenitor cells and cellular matrix production	[103,112,114]
NRP1	Induces endothelial cell migration and regulates other proangiogenic actions through the VEGF family and PDGFR	[113]
microRNAs	Bone healing function	Ref.
miR-10a	Improves mesenchymal stem cell differentiation capacity of hBM-MSCs and reduces cell senescence	[118]
miR-10b	Increases in vitro migration of BM-MSCs	[119]
miR-218, miR-92a and miR-199b	Enhance osteoblast differentiation of BM-MSCs	[120,122]
miR-217 and miR-34	Promote proliferation and osteoblast differentiation of BM-MSCs	[120,121]
miR-375, miR-216a, let-7c and miR-22	Stimulate osteogenic differentiation of hAD-MSCs	[124,125,127]
miR-196a	Increases osteogenic differentiation of hAD-MSCs and osteogenic activity of osteoblasts	[106,126]
miR-494	Induces endothelial cell migration	[109]
miR-129 and miR-136	Promote endothelial cell proliferation	[129]
miR-130a, miR-135b, let-7f and miR27b	Promote vascular tube formation	[117,130,132]
miR-1246	Enhances endothelial migration and tube formation	[131]
miR-23a and miR-424	Cause migration, proliferation and tube formation of endothelial cells	[133,134]
miR-214	Fosters prevention of cell senescence, migration and tube formation in endothelial cells, and RANKL-induced osteoclast differentiation in BMMs	[136,137]
miR-148a	Stimulates osteoclastogenesis in early osteoclast progenitors	[138]
miR-27a, miR-206, miR-29b, miR-181a and miR-302a	Induce osteogenic activity of osteoblasts	[106,139-141]
miR-21	Assists osteogenic differentiation, migration and senescence prevention in BM-MSCs; migration and proliferation of fibroblasts; migration, proliferation and ability to form endothelial tubes in endothelial cells; and RANKL-induced osteoclastogenesis in BMMs	[142-146]

MSC: Mesenchymal stem cell; EVs: Extracellular vesicles; MCP: Monocyte chemotactic protein; SDF-1 α: Stromal cell-derived factor-1 α; IL-6: Interleukin-6; FGF-2: Fibroblast growth factor-2; VEGF: Vascular endothelial growth factor; ANGPTL: Angiopoietin-related protein; IGF: Insulin-like growth factor; TGF-β1: Transforming growth factor–β1; NRP1: Neuropilin 1; hAD: Human adipose; BM: Bone marrow; BMM: Bone marrow monocytes; RANKL: Receptor activator of nuclear factor kappa ligand.