Angiogenesis in a 3D model containing adipose tissue stem cells and endothelial cells is mediated by canonical Wnt signaling

Abstract

Adipose-derived stromal cells (ASCs) have gained great attention in regenerative medicine. Progress in our understanding of adult neovascularization further suggests the potential of ASCs in promoting vascular regeneration, although the specific cues that stimulate their angiogenic behavior remain controversial. In this study, we established a three-dimensional (3D) angiogenesis model by co-culturing ASCs and endothelial cells (ECs) in collagen gel and found that ASC-EC-instructed angiogenesis was regulated by the canonical Wnt pathway. Furthermore, the angiogenesis that occurred in implants collected after injections of our collagen gel-based 3D angiogenesis model into nude mice was confirmed to be functional and also regulated by the canonical Wnt pathway. Wnt regulation of angiogenesis involving changes in vessel length, vessel density, vessel sprout, and connection numbers occurred in our system. Wnt signaling was then shown to regulate ASC-mediated paracrine signaling during angiogenesis through the nuclear translocation of β-catenin after its cytoplasmic accumulation in both ASCs and ECs. This translocation enhanced the expression of nuclear co-factor Lef-1 and cyclin D1 and activated the angiogenic transcription of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF), and insulin-like growth factor 1 (IGF-1). The angiogenesis process in the 3D collagen model appeared to follow canonical Wnt signaling, and this model can help us understand the importance of the canonical Wnt pathway in the use of ASCs in vascular regeneration.

Precise Intradermal Injection of Nanofat-Derived Stromal Cells Combined with Platelet-Rich Fibrin Improves the Efficacy of Facial Skin Rejuvenation

“…ASCs have outstanding self-renewal potential, paracrine function, and the capacity to differentiate into multiple phenotypes. Some data have suggested the application of ASCs in lesions induces healing because of the role of ASCs in stimulating angiogenesis, which is attributed to their endothelial differentiation and release of several cytokines under specific conditions [21-24]. …”

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

“…In mice, endothelial cells in vessels within the adipose tissue may give rise to new adipocytes coupled via tight junction proteins at the very early stages of their differentiation in vivo ( Tran et al, 2012 ). Pro-angiogenic activity of adipose niche cells has been confirmed numerous times in vitro : 14 days coculture of mice endothelial cells and ASCs drives Wnt-regulated angiogenesis and functional vessel formation in 3D collagen matrices ( Cai et al, 2017 ), ASCs support greater sprouting of endothelial cells being cocultured on bioengineered polycaprolactone/gelatin nanofibrous scaffolds ( Kook et al, 2018 ), and coculture of ASCs with adipose-derived microvascular endothelial cells results in enhanced vascular network formation during 14 days of incubation period in vitro ( Freiman et al, 2016 ).…”

The co-culture of ASCs and EPCs promotes vascularized bone regeneration in critical-sized bone defects of cranial bone in rats

“…It has been found in previous studies that EPCs can enhance the osteogenic activity of pre-osteoblasts [15] and play an important role in bone formation and repair [16,17]. Adipose-derived mesenchymal stem cells (ASCs) are extracted from adipose tissue with high proliferative capability and multi-differential potential [18,19]. Compared with stem cells derived from other tissues, ADSCs have the unique advantages of a wide range of tissue sources, easy availability, and small damage to donor site [20].…”