TABLE 4.
MSC-sEVs stimulate angiogenesis by regulating vascular endothelial cells in wound healing.
| MSC source | Isolation | Target cells/conditions | Functional cargo | Molecules/Pathways affected | Key functions/Downstream genes | Ref |
|---|---|---|---|---|---|---|
| BM | Ultracentrifugation | HUVECs (normal and chronic wounds) | STAT3 | p-ERK1/2↑, p-Akt↑, p-STAT3↑, HGF↑, IGF1↑, NGF↑, SDF1↑ | enhancement of proliferation and migration HUVECs | Shabbir et al. (2015) |
| AT | Ultracentrifugation | HUVECs | MiR-31 | FIH1↓, CD31↑ | Enhanced angiogenic ability of HUVECs | Kang et al. (2016) |
| Nrf2-OE-AT | Co-Precipitation | EPC in vitro, diabetic foot ulcer in rats | Nrf2 | SMP30↑, VEGF↑, P-VEGFR2/VEGFR2↑ | Promoted cell viability, migration and angiogenesis both in vitro and in vivo | Li et al. (2018) |
| Urinary | Ultrafiltration | cutaneous wound in diabetic mice; HMECs | DMBT1 | VEGFA↑, p-AKT↑, CD31↑ | Elevated angiogenic responses in vitro and angiogenesis in vivo | Chen et al. (2018b) |
| BM | Polymer precipitation; Ultracentrifugation | HUVECs | Wnt3a | — | Enhanced proliferation, migration and angiogenesis in vitro | McBride et al. (2017) |
| AT | Ultracentrifugation | HUVECs immunodeficient mice | MiR-125a | DLL4↓, Ang1↑, Flk1↑ | Activated angiogenesis in vitro and in vivo | Liang et al. (2016) |
| Modified-AT | Ultrafiltration Ultracentrifugation | Diabetic wounds in mice, EPC | mmu_circ_0000250 | miR-128-3p↓, SIRT1↑ | Activated autophagy and proangiogenic abilities and suppressed apoptosis in vitro; increased neovascularization in vivo | Shi et al. (2020) |
| Modified synovium | Ultracentrifugation | cutaneous wound in diabetic rats; HMECs | MiR-126 | p-AKT↑, p-ERK1/2↑ | Stimulated angiogenesis in vivo; activated proliferation, migration and tube formation of HMEC-1 | Tao et al. (2017) |
| huc | Ultracentrifugation | deep second-degree burn injury in rats; HUVECs | Ang-2 | CD31↑ | Enhanced migration and tube formation of HUVECs and angiogenesis in vivo | Liu et al. (2021) |
| huc | Ultracentrifugation | cutaneous wound in diabetic mice; HUVECs | Wnt4 | PCNA↑, cyclin D3↑, N-cadherin↑, β-catenin↑, E-cadherin↓ | Elevated proliferation, migration and angiogenic abilities of HUVECs; activated neovascularization in vivo | Zhang et al. (2015a) |
| Modified AT | affinity chromatography | HUVECs | MiR-21 | PTEN↓, p-AKT↑, p-ERK1/2↑, HIF-1α↑, SDF↑,VEGFA↑ | stimulated vascularization | An et al. (2019) |
| Thrombin pretreated hucb | Ultracentrifugation | cutaneous wound in rats; HUVECs | angiogenin, angiopoietin-1, HGF, VEGF | p-ERK1/2↑, p-AKT↑ | Enhanced proangiogenic activity in vitro and accelerated neovascularization and cutaneous wound healing in vivo | Sung et al. (2019) |
| Huc | Ultracentrifugation | cutaneous wound in diabetic mice; HUVECs | miR-17-5p | PTEN↓, p-AKT↑, HIF-1α↑, VEGF↑ | Boosted proliferation and migration, tube formation of HUVECs and neovascularization in vivo | Wei et al. (2021) |
| ATV-pretreated BM | Ultracentrifugation | Skin wounds in diabetic rats, HUVECs | MiR-221 | PTEN↓, p-AKT↑, p-eNOs↑, VEGF↑ | Promoted proliferation and migration activity of HUVECs and neovascularization in vivo | Yu et al. (2020) |
| HOTAIR-OE-BM | Ultracentrifugation | Skin wound in rats and diabetic mice; HUVECs, HMECs | Lnc HOTAIR | VEGF↑ | Improved angiogenesis and accelerated wound healing, boosted pro-angiogenic activities of endothelial cells in vitro | Born et al. (2021) |
| BM | Ultracentrifugation | 3D human Skin Organotypic model; ECs | Ang2, ET-1, EG-VEGF/PK1, Persephin, uPA | Promoted angiogenesis in model and enhanced angiogenic ability in vitro | Tutuianu et al. (2021) | |
| AT | Ultracentrifugation | HUVECs, cutaneous wounds in aged and diabetic mice | MiR-146a | p-Src↓, p-VE-cadherin↓, p-caveolin-1↓, p21↓, p16↓, p53↓ | Decreased SASP, rescued angiogenesis in vitro; promoted neovascularization in wound healing | Xiao et al. (2021) |
| BM | Ultracentrifugation | EPCs; ischemic hindlimb in aged mice | MiR-126a | Spred-1↓, p16Ink4a↓, CD31↑ | Rejuvenation of aged EPCs, attenuated SA-β-Gal expression | Wang et al. (2020) |
BM, bone marrow; HUVEC, human umbilical vein endothelial cell;,STAT3, signal transduction and activators of transcription 3; Erk1/2, extracellular regulated kinase 1/2; AKT, protein kinase B; HGF, hepatocyte growth factor; IGF-1, insulin like growth factor 1; NGF, nerve growth factor; SDF1, stromal cell-derived factor1; HiPSC, human induced pluripotent stem cell; FIH1, factor-inhibiting HIF-1; Nrf2, nuclear factor erythroid 2–related factor 2; EPC, endothelial progenitor cell; SMP30, senescence marker protein 30; HMEC, human microvascular endothelial cell; DMBT1, deleted in malignant brain tumors 1; VEGFA, vascular endothelial growth factor A; DLL4, delta-like 4; HGF, hepatic growth factor; VEGF, vascular endothelial growth factor; HOTAIR, HOX, transcript antisense RNA; EC, endothelial cells; Ang-2, angiopoietin-2; ET-1, endothelin; EG-VEGF/PK1, endocrine gland derived vascular endothelial growth factor; uPA, urokinase-type plasminogen activator; hAAM, human acellular amniotic membrane.