The Proliferation and Differentiation of Adipose-Derived Stem Cells in Neovascularization and Angiogenesis

Abstract

Neovascularization and angiogenesis are vital processes in the repair of damaged tissue, creating new blood vessel networks and increasing oxygen and nutrient supply for regeneration. The importance of Adipose-derived Mesenchymal Stem Cells (ASCs) contained in the adipose tissue surrounding blood vessel networks to these processes remains unknown and the exact mechanisms responsible for directing adipogenic cell fate remain to be discovered. As adipose tissue contains a heterogenous population of partially differentiated cells of adipocyte lineage; tissue repair, angiogenesis and neovascularization may be closely linked to the function of ASCs in a complex relationship. This review aims to investigate the link between ASCs and angiogenesis/neovascularization, with references to current studies. The molecular mechanisms of these processes, as well as ASC differentiation and proliferation are described in detail. ASCs may differentiate into endothelial cells during neovascularization; however, recent clinical trials have suggested that ASCs may also stimulate angiogenesis and neovascularization indirectly through the release of paracrine factors.

Keywords: adipose; angiogenesis; differentiation; stem; vascularization.

Figure 1

Cell fate of mesenchymal stem cells related to angiogenesis and adipogenesis. MSCs in adipose tissue may differentiate into a variety of cell types including endothelial cells, smooth muscle cells as well as white or brown adipocytes and thereby contribute to angiogenesis and neovascularization. In adipogenesis, Myf5+ and Myf5- cells mark two distinct populations which diverge early in adipogenesis. Myf5+ cells will differentiate into brown adipose tissue while Myf5- will differentiate into white adipose tissue. CD34 is an endothelial cell marker, while MYOCD is a marker for smooth muscle cell differentiation [20,21]. (Created with BioRender).

Figure 2

Mechanisms regulating adipose stem cells expansion, including activation of target CCAAT/enhancer-binding proteins and PPARγ through recruitment of transcription factors including activators of transcription CREB, GR and STAT5, resulting in change of conformation of active sites on target proteins. Activated target CCAAT/enhancer-binding proteins regulate PPARγ through Sth40 mediated inhibition of C/EBPβ, while PPARγ itself stimulates expansion of adipose stem cells, by SWELL1/LRCC8 mediated activation of SWELL1 mediated VRAC signaling pathway. (Created with BioRender).

Figure 3

(A) Vascular endothelial growth factor (VEGF) stimulates non-coding miR-296, which then lowers the expression of platelet-derived growth factor (HGS). HGS is responsible for controlling the degradative sorting of VEGFR and platelet-derived growth factor receptor (PDGFR), so their protein expression levels are regulated. However, since miR-296 lowers HGS, then VEGF2 and PDGFRβ levels increase, stimulating VEGF activity. (B) Anti-angiogenic treatment is used to downregulate the activity of VEGFR and PDGFR, which decreases their protein levels, which could combat the effects of the miR-296 cycle [113]. (Created with BioRender).