Systems biology approach to identify alterations in the stem cell reservoir of subcutaneous adipose tissue in a rat model of diabetes: effects on differentiation potential and function

Abstract

Aims/hypothesis Autologous progenitor cells represent a promising option for regenerative cell-based therapies. Nevertheless, it has been shown that ageing and cardiovascular risk factors such as diabetes affect circulating endothelial and bone marrow-derived progenitor cells, limiting their therapeutic potential. However, their impact on other stem cell populations remains unclear. We therefore investigated the effects of diabetes on adipose-derived stem cells (ASCs) and whether these effects might limit the therapeutic potential of autologous ASCs. Methods A systems biology approach was used to analyse the expression of genes related to stem cell identification in subcutaneous adipose tissue (SAT), the stromal vascular fraction and isolated ASCs from Zucker diabetic fatty rats and their non-diabetic controls. An additional model of type 2 diabetes without obesity was also investigated. Bioinformatic approaches were used to investigate the biological significance of these changes. In addition, functional studies on cell viability and differentiation potential were performed. Results Widespread downregulation of mesenchymal stem cell markers was observed in SAT of diabetic rats. Gene expression and in silico analysis revealed a significant effect on molecules involved in the maintenance of pluripotency and self-renewal, and on the alteration of main signalling pathways important for stem cell maintenance. The viability and differentiation potential of ASCs from diabetic rats was impaired in in vitro models and in in vivo angiogenesis. Conclusions/interpretation The impact of type 2 diabetes on ASCs might compromise the efficiency of spontaneous selfrepair and direct autologous stem cell therapy.

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats

“…Except for similarity to MSC from umbilical cord and bone marrow, ASC have great advantages for cell preparation because of the easier and safer access to adipose tissue and their higher proliferative activity with greater production of vascular endothelial cell growth factor (VEGF) and hepatocyte growth factor (HGF) than bone marrow derived MSC (BM-MSC) [14]. Tissue source has a greater influence on gene expression profiles than the different culture methods.…”

“…The higher level of heterogeneity of ASC suggests that those cells do represent MSC that have more lineage capabilities than BM-MSC [16,17]. However, the effects of diabetes on ASC leads to a gradual depletion of the ASC pool, as with BM-MSC [18,19]. More studies have confirmed that MSC therapy could effectively ameliorate both type 1 and type 2 diabetes [20][21][22], while there are few reports on the effects of ASC on the late phase of type 2 diabetes.…”

Notch Signaling Pathway Activation in Normal and Hyperglycemic Rats Differs in the Stem Cells of Visceral and Subcutaneous Adipose Tissue

“…WATs [epicardial (EC WAT ), epididymal (ED WAT ), mesenteric (ME WAT ), retroperitoneal (RP WAT ), and SC WAT ] were excised and processed to obtain ASCs as previously described technique [37] and it is detailed in Supplementary Methods (Isolation and culture of ASCs heading).…”

Adipose-derived Mesenchymal Stem Cells and Their Reparative Potential in Ischemic Heart Disease

“…Recently, our group has reported that type 2 diabetes mellitus negatively affects the pluripotency and self-renewal capacities of ADSCs, altering the main pathways involved in the maintenance of stem cells and their differentiation and angiogenic potentials. 37 Obesity has also been described as a disease that affects ADSCs. Van Harmelen et al 38 found that the adipogenic differentiation capacity of ADSCs of subcutaneous mammary adipose tissue is decreased in women with a high body mass index.…”