Adipose mesenchymal stem cells from different fat depots in obese and lean subjects have different microRNA signatures involved in their differentiation into endothelial cells

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III - Fondo de Investigaciones Sanitarias (FIS) P20/01517 to GA and Spanish Ministry of Science and Innovation PID 2019-107160RB-I00 to LB. All grants were co-financed by European Union Funds, Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa".

Background/Introduction: Cell-based regenerative medicine has emerged as the forefront therapeutic procedure to improve ischemic tissue recovery. This approach is based on the usage of multilineage stem cells that can contribute to tissue regeneration. Revascularization of ischemic tissues is one of the objectives of cell therapy1,2. In this regard, we have investigated adipose-derived stem cells (ASCs), multipotent adult mesenchymal stems cells, as a cell source for therapy because of their capability to differentiate into endothelial cells (ECs)3–5. The regulatory mechanisms that drive the differentiation to EC are under investigation.

Our hypothesis is that microRNAs (miRNAs) are involved in ASC to EC differentiation by a defined genetic signature in each fat tissue depot. The understanding of these mechanisms may be used to promote neovascularization in ischemic tissue.

Human ASCs from white adipose tissue (WAT) were obtained by surgical procedures from lean and obese patients. Importantly, subcutaneous-WAT and visceral-WAT were obtained from the same obese patient. ASCs from fat depots of lean and obese subjects where induced to differentiate into endothelial cells. The expression of 2025 pre-miRNAs and 2578 mature miRNAs was assessed using miRNA arrays in four biological replicates.

Differentially up-regulated and down-regulated miRNAs were obtained from the respective fat depots. Seven of the most differentially expressed miRNAs were validated by qRT-PCR. The miRNA targets involved in the regulation of angiogenesis were selected by bioinformatic algorithms. We have identified 4 miRNAs that promote and stimulate ASCs differentiation into cells with endothelial cell-like phenotype through the regulation of FGFR1, NRP2, MAPK1, TGFB2, ETS1 and PTPN9.

In summary, the regulation of ASCs to EC differentiation (endotheliogenesis) involves a distinctive miRNA signature relying on WAT depot.