Plasticity of Adipose Tissue-Derived Stem Cells and Regulation of Angiogenesis

Abstract

Adipose tissue is recognized as an important organ with metabolic, regulatory, and plastic roles. Adipose tissue-derived stem cells (ASCs) with self-renewal properties localize in the stromal vascular fraction (SVF) being present in a vascular niche, thereby, contributing to local regulation of angiogenesis and vessel remodeling. In the past decades, ASCs have attracted much attention from biologists and bioengineers, particularly, because of their multilineage differentiation potential, strong proliferation, and migration abilities in vitro and high resistance to oxidative stress and senescence. Current data suggest that the SVF serves as an important source of endothelial progenitors, endothelial cells, and pericytes, thereby, contributing to vessel remodeling and growth. In addition, ASCs demonstrate intriguing metabolic and interlineage plasticity, which makes them good candidates for creating regenerative therapeutic protocols, in vitro tissue models and microphysiological systems, and tissue-on-chip devices for diagnostic and regeneration-supporting purposes. This review covers recent achievements in understanding the metabolic activity within the SVF niches (lactate and NAD+ metabolism), which is critical for maintaining the pool of ASCs, and discloses their pro-angiogenic potential, particularly, in the complex therapy of cardiovascular and cerebrovascular diseases.

Keywords: adipocyte; adipose tissue; angiogenesis; endothelial cells; stem cell; vasculature-on-chip.

FIGURE 1

Schematic illustration of intercellular communications within the stromal vascular fraction (SVF) with the focus on adipocyte- and ASCs-mediated regulation of angiogenesis. Within the SVF, adipocytes (Adipo) and preadipocytes (pre-Adipo) serve as a major source of glycolytically produced lactate. Elevated levels of lactate in the extracellular space support proangiogenic activity of ASCs whose maintenance also depends on glycolytic flux and mitochondrial respiration. Some other locally produced molecules [hydrogen sulfide H₂S in pericytes (P) or adipocytes; adenosine and interleukin-8 (IL-8) in ASCs or macrophages] contribute to angiogenesis control within the SVF. As a result, activity of endothelial cells (ECs) and EPCs provides angiogenesis and vascular remodeling adjusted to the current metabolic and functional needs of adipose tissue.

FIGURE 2

Current approaches to vascular engineering strategies utilizing ASCs as a source of vascular and perivascular cells. Isolated ASCs might be used for: (i) systemic (intravenous) or local (i.e., intracoronary) administration; (ii) in vitro differentiation toward the desired phenotype (myocardial cells, pacemakerlike cells, endothelial cells, smooth muscle cells, neuronal cells, etc.); (iii) establishment of 3D models and microfluidic systems in vitro; and (iv) development of artificial clonogenic niches for controlled in vitro production of stem cells supported by microvascular network). Then, all these approaches could be used in: (i) regeneration therapeutic protocols aimed to re-establish tissue components, including (micro)vessels; (ii) drug/xenobiotic testing in vitro; (iii) diagnostic devices in “lab-on-chip format”; (iv) supporting devices for grafted cells (as vascular scaffolds) or bioreactors for efficient generation of stem and progenitor cells in vitro.