Table 2.
Extracellular vesicles derived from stem cells promote angiogenesis in chronic wound healing
| EVs source | EVs type | EVs isolation | Experimental model (target cells/animal models) | Functional cargo | Molecules/pathways activated | Key functions/downstream genes | Reference |
|---|---|---|---|---|---|---|---|
| BM-MSCs | Exosomes |
Differential centrifugation Ultracentrifugation |
In vitro (HUVECs) | STAT3 | Akt, ERK, and STAT3 | HGF, IL-6, IGF-1, NGF and SDF1↑ | Shabbir et al. [54] |
| BM-MSCs | Exosomes |
Differential centrifugation PEG-US-S purification Ultracentrifugation |
In vitro (HUVECs) | Wnt3a | Wnt pathway | CD63+ exosomes are a significant carrier of exterior Wnt3a which results in angiogenesis in vitro. | McBride et al. [55] |
| ADSCs | MVs |
Differential centrifugation 100 KDa molecular filtration Ultracentrifugation |
In vitro (HUVECs) In vivo (mice/full-thickness wounds model) |
/ | PI3K-AKT and ERK signaling pathways | VEGFA, PDGFA, EGF and bFGF↑ | Ren et al. [56] |
| ADSCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HUVECs) In vivo (male BALB/c nude mice) |
miR-125a | Speculated to Notch signaling pathways |
proangiogenic genes Ang1 and Flk1 ↑ anti-angiogenic genes Vash1, TSP1 and DLL4 ↓ |
Liang et al. [57] |
| ADSCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HUVECs) In vivo (nude mice) |
/ | PKA signaling pathway |
proangiogenesis gene Angpt1 and Flk1↑ VEGF↑ anti-angiogenic gene Vash1↓ |
Xue et al. [58] |
| UC-MSCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HMECs) In vivo (male C57BL/6 mice/full-thickness excisional skin wounds model) |
miR-21-3p | PI3K/Akt and ERK1/2 signaling | PTEN and SPRY1↓ | Hu et al. [59] |
| UC-MSCs | Exosomes |
Differential centrifugation 100 kDa molecular weight cut-off (MWCO) hollow fiber membrane Ultracentrifugation |
In vitro (EA.hy926 cells) In vivo(rats/deep second-degree burn wounds model) |
Wnt4 | Wnt pathway | Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects. | Zhang et al. [60] |
| PMSCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HMECs) In vivo (nude mice/auricle ischemic injury model) |
/ | / | PMSC-Exos enhanced angiogenesis in vitro and in vivo | Komaki et al. [61] |
| iPSCs | Exosomes | MagCapture Exosome Isolation Kit | In vivo (male C57BLKS/J-Leprdb (db/db) mice/full-thickness excisional skin wounds and diabetes model) | / | / | iPSC-Exos significantly increased micro-vessel of full-thickness excisional skin wounds in diabetes mice | Kobayashi et al. [62] |
| iPSCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HUVECs) In vivo (female Sprague-Dawley rats/full-thickness skin defect model) |
/ | / | iPSC-Exos can increase proliferation, migration, and tube formation of HUVECs in a dose-dependent manner | Zhang et al. [63] |
| EPCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HMECs) In vivo(male Sprague-Dawley rats) |
/ | / |
eNOS, IL-8, ANG-1, E-selectin, VEGFA, VEGFR-2, HIF- 1a, CXCL16 and PDGFA↑ PDGFB and MMP-9↓ |
Li et al. [64] |
| EPCs | Exosomes |
Differential centrifugation 0.2-μm pore membrane filtration Ultracentrifugation |
In vitro (HMECs) In vivo (male Sprague-Dawley rats/diabetic model) |
/ | / |
aFGF, eNOS, IL-8, ANG-1, E-selectin, VEGFA, VEGFR-2 and CXCL-16↑ MMP-9↓ |
Li et al. [65] |
Abbreviation: BM-MSCs bone marrow-mesenchymal stem cells, ADSCs adipose-derived stem cells, UC-MSCs umbilical cord mesenchymal stem cells, PMSCs placenta tissue mesenchymal stem cells, iPSCs induced pluripotent stem cells, EPCs endothelial progenitor cells, MVs microvesicles, PEG-UC-S polyethylene glycol-sucrose cushion method, HUVECs human umbilical vein endothelial cells, HMECs human microvascular endothelial cells, HGF hepatocyte growth factor, IL-6 interleukin-6, IGF-1 insulin-like growth factor-1, NGF nerve growth factor, SDF1 stromal-derived growth factor-1, VEGFA vascular endothelial growth factor A, PDGFA platelet-derived growth factor subunit A, EGF epidermal growth factor, bFGF basic fibroblast growth factor, DLL4 delta-like 4, VEGF vascular endothelial growth factor, IL-8 interleukin-8, ANG-1 angiopoietin-1, VEGFR-2 vascular endothelial growth factor receptor 2, HIF-1a hypoxia-inducible factor 1 alpha, PDGFA platelet-derived growth factor subunit A, PDGFB platelet-derived growth factor subunit B, MMP-9 matrix metallopeptidase 9