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