Table 3.
Extracellular vesicles derived from stem cells promote angiogenesis in myocardial ischemia
| EVs source | EVs type | EVs isolation | Experimental model (target cells/animal models) | Functional cargo | Molecules/pathways activated | Key functions/downstream genes | Reference |
|---|---|---|---|---|---|---|---|
| CDCs | Exosomes |
Differential centrifugation Exoquick Exosome Precipitation Solution Ultracentrifugation |
In vitro (HMECs) In vivo (male SCID mice) |
miR-146a | / | Enhanced angiogenesis and the density of micro-vessels both in vitro and in vivo | Ibrahim et al. [93] |
| CDCs | Exosomes |
Ultracentrifugation Exoquick exosome precipitation solution |
In vitro (HUVECs) In vivo (male SCID-beige mice) |
/ | / |
In vitro: stimulate angiogenesis in a HUVEC angiogenesis assay. In vivo: stimulated capillary reorganization. |
Lang et al. [94] |
| CDCs | Exosomes |
Differential centrifugation Ultracentrifugation |
In vitro (HUVECs) | miR-126, miR-130a, miR-210 | / |
Speculate: miR-210→EENA3↓→ tube formation↑ miR-130a→GAX and HoxA5↓→ VEGF and VEGFR2↑→tube formation↑ miR-126→VEGF and bFGF↑, Spred-1↓→ tube formation↑ |
Namazi et al. [95] |
| CDCs | Exosomes |
450 nm pore membrane filtration PEG ultrafiltration Centrifugation |
In vivo (female adult Yucatan mini-pigs/MI model) | / | / | decreased acute ischaemia-reperfusion injury, and halt chronic post-MI adverse remodeling in pigs | Gallet et al. [96] |
| BM-MSCs | Exosomes |
ExoQuick-TC reagent Centrifugation |
In vitro (HUVECs) In vivo (female Sprague-Dawley rats/MI model) |
/ | / | Exosomes accounted for the cardioprotection through the formation of new blood vessels. | Teng et al. [97] |
| BM-MSCs | Exosomes | ExoQuick-TC reagent |
In vitro (HUVECs) In vivo (female Sprague-Dawley rats/MI model) |
CXCR4 | PI3K/Akt signaling pathway |
VEGF ↑ Cardiomyocyte survival↑ |
Kang et al. [98] |
| BM-MSCs | Exosomes |
Differential centrifugation Ultracentrifugation |
In vitro (HUVECs/HMECs) In vivo (male C57bl/6 mice) |
EMMPRIN | ERK/Akt signaling pathway | EMMPRIN has powerful proangiogenic effects both in vitro and in vivo | Vrijsen et al. [99] |
| UC-MSCs | Exosomes |
Differential centrifugation 100 kDa molecular weight cut-off hollow fiber membrane Ultracentrifugation |
In vitro (EA.hy926 cells) In vivo (male Sprague-Dawley rats/MI model) |
/ | / | protect myocardial cells and accelerate heart repair by angiogenesis after ischemic injury. | Zhao et al. [100] |
| ADSCs | MVs |
Differential centrifugation Ultracentrifugation |
In vitro (HUVECs) In vivo (male C57BL/6 J mice and nude mice) |
miR-31 | / | FIH1↓ | Kang et al. [101] |
| EnMSCs | Exosomes |
0.22-μm pore membrane filtration Exosome isolation reagent Centrifugation |
In vitro (HUVECs) In vivo (male Sprague-Dawley rats/MI model) |
miR-21-5p | PTEN-Akt pathway |
PTEN↓ Akt and VEGF↑ |
Wang et al. [102] |
| ESCs | Exosomes | Ultracentrifugation |
In vitro (HUVECs) In vivo (male C57BL/6 mice/MI model) |
/ | / |
In vitro: increased tube formation; In vivo: decreased infarct size. |
Khan et al. [103] |
| iPSC | MVs |
Differential centrifugation Ultracentrifugation |
In vitro (CECs) In vivo (C57BL/6 mice/MI model) |
/ | / |
In vitro: EVs impart cytoprotective properties to cardiac cells In vivo: induce superior cardiac repair with regard to LV function and vascularization. |
Adamiak et al. [104] |
|
iPSC-Pg iPSC-CM |
Exosomes | Ultracentrifugation |
In vitro (HUVECs) In vivo (nude mice/MI model) |
/ | / | EV may promote cell survival, proliferation of resident cardiac cells, and angiogenesis thereby improving left ventricular function. | EI Harane et al. [105] |
| CD34+ cells | Exosomes |
Differential centrifugation Ultracentrifugation |
In vitro (HUVECs) In vivo (nude mice) |
miR-126, miR-130a | / |
In vitro: promote tube formation in HUVECs In vivo: induced the formation of vessel-like endothelial structures in corneal angiogenesis assays. |
Sahoo et al. [106] |
Abbreviation: CDCs cardiosphere-derived cells, BM-MSCs bone marrow-mesenchymal stem cells, UC-MSCs umbilical cord mesenchymal stem cells, ADSCs adipose-derived stem cells, EnMSCs human endometrium-derived mesenchymal stem cells, ESCs embryonic stem cells, iPSC-Pg human-induced pluripotent stem cell-derived cardiovascular progenitors, iPCS-CM human-induced pluripotent stem cell-derived cardiomyocytes, MVs microvesicles, HMECs human microvascular endothelial cells, HUVECs human umbilical vein endothelial cells, CECs murine cardiac endothelial cells, SCID severe combined immunodeficient, MI myocardial infarction model, EMMPRIN extracellular matrix metalloproteinase inducer, FIH1 hypoxia-inducible factor 1-alpha inhibitor