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Table 1 MSC trophic activities relevant to musculoskeletal therapy: mechanistic insights from in-vitro and host tissue studies

From: Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies

System and reference In vitro/host Cell sources Observed trophic activity Mechanistic insights
Angiogenesis [84] IV Human BM-MSCs; UCB-ECs MSCs encouraged EC migration, proliferation, and tubule formation GHK (osteonectin peptide) induces MSC-VEGF secretion
Angiogenesis [81] IV Human BM-MSCs (commercial); microvascular ECs MSC culture on stiff, fibronectin-coated surfaces encouraged EC spreading/tubule formation Actomyosin contractility increased MSC expression of proangiogenic factors (angiogenin, VEGF, and IGF)
Angiogenesis [105] IV Human BM-MSCs (commercial); UV-ECs EC-MSC coculture increased MSC-myogenic and EC-PLAU, EC-FGF, and EC-NF-kB-regulated gene expression • MSC IL-1β and IL-6 regulate EC NF-kB target genes, including P-selectin, CCL23, and CXCL2/3
• EC TGF-β1/3 may regulate MSC myogenic differentiation
Angiogenesis [107] IV/mouse Human BM-MSCs (commercial); UV-ECs • IV: EC-MSC (vs EC) cultures on degradable scaffolds expressed higher perivascular markers IV: cocultures upregulated VEGF and ANG1 while downregulating ANG2
• Host angiogenic and perivascular markers, except vessel diameter and density, were equivalent between EC/MSC-EC implants
Angiogenesis [73] IV/mouse Human iMSCs (medium change of iPSCs); UV-ECs • iMSC exosomes promoted EC migration, proliferation, and dose-dependent tubule formation (IV) iMSCs induced EC expression of proangiogenic molecules, including VEGF, TGF-β1, and ANG1
• Exosome treatment correlated with modest functional improvement, better perfusion and tissue damage scores, increased CD31/CD34+ cells
Angiogenesis (hindlimb ischemia) [22] Mouse Mouse AD-MSCs (plastic adherence); BM-MSCs (plastic adherence); BM-iMSCs (immunodepletion) • BM-MSCs maximally decreased inflammatory cell invasion IV: BM-MSCs expressed the highest levels of tested chemokines, vessel stabilizing, and matrix-remodeling factors
• MSCs were associated with smaller lesions, more mature neovascularization, and increased perfusion
Neurovascular system (fibrin conduit, resection) [116] Rat Human AD-MSCs (plastic adherence); DRG; UV-EC • Medium cocktail-stimulated MSCs enhanced DRG neurite extension and EC-tubule formation Stimulated MSCs produced increased VEGF, ANG1, NGF, BDNF, and GDNF
• Stimulated and unstimulated MSCs encouraged neurite extension
Neurogenesis [167] IV Rat BM-MSCs (plastic adherence) Spinal cord tissue–MSC coculture supported neurite outgrowth Cocultured MSCs produced NGF, BDNF, and GDNF, maximally supporting neurite extension
Neurogenesis (spinal nerve ligation) [123] Rat Rat BM-MSCs (commercial) MSC-treated rats displayed decreased hyperalgesia and increased pain threshold TUBB3, GFAP, and αSMA and STRO1+ MSCs engrafted into DRGs
Neurogenesis (sciatic crush) [124] Mouse Human AD-MSCs and AM-MSCs (commercial) • AM-MSC-treated groups exhibited higher recovery, coordination, and perfusion scores (4 weeks) Nerves injected with AM-MSCs versus AD-MSCs or PBS produced more ANG1, FGF1, IGF1, and VEGFA
• MSCs localized in the epineurium and perivascular area
Distraction Osteogenesis (DO) [59] Mouse Human BM-MSCs (commercial) • MSC and MSC-CM accelerated DO healing • IV: IL-3/IL-6/CCL5/SDF1 recruited mononuclear cells, contributed to enhanced mineralization
• MSC-CM recruited more vessels
• MCP1/MCP3 but not SDF1 were critical for SC-CM osteogenic activity
Osteogenesis [168] Mouse Human AD-MSCs and BM-MSCs; UCB-ECs • MSC-EC cotransplantation increased MSC engraftment PDGFBB/PDGFRβ receptor activity regulates MSC engraftment and differentiation in the presence of ECs
• Cotransplantation restricted MSC multipotency, enhanced MSC source-related differentiation abilities, and maintained MSC proliferation capacity
Osteoporosis (lupus associated) [60] Mouse Human BM-MSCs and DP-MSCs • MSC injections improved osteoporosis-related bone scores IL-17 removal following MSC injection maintains osteoclast immaturity
• MSCs lowered osteoclast differentiation (IV)
Osteogenesis [169] Rat Rat BM-MSCs (centrifugation and plastic adherence) Fibrin-loaded MSC recruited host macrophages to fill long bone defect by 4 weeks Implanted MSCs increased early expression of VEGF and decreased later expression of CD45, IL-6, IL-1β, TNF-α, and IL-10
Osteogenesis, chondrogenesis, angiogenesis [170] IV Human BM-MSCs (density gradient) and human embryonic stem cell MSCs (medium/substrate changes); human aortic ECs MSC-EC cocultures proliferated and exhibited higher expression of mesenchymal differentiation transcription factors EC-produced ET1 activates MSC AKT, driving osteogenic and chondrogenic capacities
Chondrogenesis [95] IV Human BM-MSCs (density gradient) • MSCs and/or chondrocytes in fibrin gels exhibited superior mechanical properties to those cultured with OA cartilage explants IL-1β and IL-6 decreased COL production versus control cultures, except in chondrogenic cultures at longer culture times (4 weeks)
• COLI/II/III production reduced in OA cartilage–MSC or chondrocyte–MSC cocultures
Chondrogenesis [93] IV Human BM-MSCs; Human OA primary chondrocytes; bovine primary chondrocytes FGF1 caused chondrocyte proliferation • FGF1 was concentrated in places where MSCs contacted chondrocytes
Tenogenesis (enzymatic lesion) [152] Horse Horse AD-MSCs Lesions were smaller, more vascularized, and less cellular when treated with platelet concentrate-injected MSCs • Greater amount of RNA was recovered from the MSC-treated group
• No difference in anabolic and tendon-specific gene expression observed
Musculogenesis (dystrophin/utrophin) [135] IV Mouse quickly and slowly adhering MSCs (non-myogenic nmMSCs and MPCs), dKO) • dKO-MPC-dKO-nmMSC co-culture decreased global myogenic markers Soluble frizzled-related protein-1 and active β-catenin encouraged nonmyogenic differentiation of dKO-nmMSCs in gastrocnemius tissues
• dKO vs. WT-nmMSCs differentiated more efficiently along osteogenic and adipogenic lines with donor age
Musculogenesis (myofibroblast proliferation) [138] IV Human AD-MSCs and BM-MSCs (commercial); Dupuytren’s disease-derived myofibroblast (DDMF) • AD-MSCs (similar to normal skin-derived fibroblasts) decreased while BM-MSCs increased DDMF co-culture contractility AD-MSC/myofibroblast cocultures exhibited decreased COLI and αSMA
• AD-/BM-MSCs inhibited myofibroblast proliferation
• AD-MSC effects were strongest with direct or indirect contact
Musculogenesis (dystrophin) [160] Mouse Human (STRO1+) DP-MSCs; human (c-Kit+) amniotic fluid MSCs • MSCs differentiated in the presence of C2C12-formed myotubes (IV) Demethylation was critical for IV myogenic differentiation
• MSCs differentiated most efficiently with C2C12-CM
• All differentiated MSCs engrafted and improved muscle histology
Musculogenesis [137] IV Mouse BM-MSCs (centrifugation and plastic adherence) MSC-CM stimulated myoblast and satellite cell proliferation and migration, activated satellite cells, inhibited myofibroblast differentiation MSC MMP-2/9 and TIMP-1/2 support myogenic differentiation
  1. AD, adipose-derived, AM amniotic membrane, BM, bone marrow, CM conditioned medium, dKO double knockout, DP dental pulp, DRG dorsal root ganglia, EC endothelial cell, iMSCs MSCs generated from induced pluripotent stem cell (iPSC) lines via medium change, IV in vitro, MMP matrix metalloproteinase, MPC multipotent cell, MSC mesenchymal stem cell, SC stem cell, TIMP tissue inhibitor of metalloproteinase, UCB umbilical cord blood, UV umbilical vein