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