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Review
. 2021 Oct 8;22(19):10890.
doi: 10.3390/ijms221910890.

Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells

Swarna Rautiainen  1 , Timo Laaksonen  1 , Raili Koivuniemi  1
Affiliations
Review

Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells

Swarna Rautiainen et al. Int J Mol Sci. .

Abstract

Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell-cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo.

Keywords: adipose-derived mesenchymal stem/stromal cell; angiogenesis; cell transplantation; co-culture; co-transplantation; endothelial cell; extracellular vesicle; ischemia; wound healing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of angiogenesis induced by adipose-derived mesenchymal stem/stromal cells (ASCs). ASCs promote endothelial cell (EC) proliferation and migration while inhibiting apoptosis. Proliferating and migrating ECs form tubular structures, and this initial vascular network is further organized by vessel sprouting, i.e., formation of new vessels from existing ones in response to angiogenic stimuli. In mature blood vessels, ASCs regulate vascular permeability. Figure created using BioRender.
Figure 2
Figure 2
Major factors affecting adipose-derived mesenchymal stem/stromal cell (ASC) differentiation into endothelial cells (ECs). Fibroblast growth factor 2 (FGF-2) activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, leading to the phosphorylation of forkhead box protein O1 (FOXO1), which decreases its transcriptional activity. As a result, the levels of miR-145 decrease and the levels of its downstream target V-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1) increase, which upregulate the transcription of EC-related genes. VEGF, on the other hand, activates ERK signaling pathway via VEGFR2 activation, leading to upregulation of EC genes, while MMP2 and -14 induce VEGFR2 cleavage and decrease in downstream signaling. Additionally, environmental factors such as shear force, hypoxia, EC priming of ASCs and 3D culture conditions enhance endothelial differentiation of ASCs.
Figure 3
Figure 3
ASCs stimulate angiogenesis via paracrine secretion of growth factors, which regulate endothelial cells, and by differentiating into ECs expressing, e.g., CD31 and vWf, or by developing pericyte characteristics, including expression of NG2 and α-SMA. Pericytes provide an additional mechanical stimulus and support for ECs to stabilize developing vascular structures.
Figure 4
Figure 4
The miRNA cargo of ASC-EVs known to have effects on endothelial cells. Figure created using BioRender.
See this image and copyright information in PMC

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References

    1. Tousoulis D., Charakida M., Stefanadis C. Endothelial function and inflammation in coronary artery disease. Postgrad. Med. J. 2008;84:368–371. doi: 10.1136/hrt.2005.066936. - DOI - PubMed
    1. Chao C.Y.L., Cheing G.L.Y. Microvascular dysfunction in diabetic foot disease and ulceration. Diabetes/Metab. Res. Rev. 2009;25:604–614. doi: 10.1002/dmrr.1004. - DOI - PubMed
    1. Woywodt A., Gerdes S., Ahl B., Erdbruegger U., Haubitz M., Weissenborn K. Circulating Endothelial Cells and Stroke: Influence of Stroke Subtypes and Changes During the Course of Disease. J. Stroke Cerebrovasc. Dis. 2012;21:452–458. doi: 10.1016/j.jstrokecerebrovasdis.2010.11.003. - DOI - PubMed
    1. Cao Y., Sun Z., Liao L., Meng Y., Han Q., Zhao R.C. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem. Biophys. Res. Commun. 2005;332:370–379. doi: 10.1016/j.bbrc.2005.04.135. - DOI - PubMed
    1. Traktuev D.O., Merfeld-Clauss S., Li J., Kolonin M., Arap W., Pasqualini R., Johnstone B.H., March K.L. A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks. Circ. Res. 2008;102:77–85. doi: 10.1161/CIRCRESAHA.107.159475. - DOI - PubMed

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