Identification of human adipose tissue native progenitor cell subsets in distinct adipogenic states

Esteve, D.; Boulet, N.; Zakaroff-Girard, A.; Ledoux, S.; Decaunes, P.; Iacovoni, J.; Heymes, C.; Bouloumié, A.; Galitzky, J.
March 2013
Proceedings of the Physiological Society;2013, p929P
Conference Proceeding
Adipogenesis plays an important role in adipose tissue (AT) expansion and in adipocyte turnover. This process involving transcriptional activation/repression netwoks is defined by the shift of undifferentiated and non-committed mesenchymal cells to differentiated metabolically active adipocytes, through different states as committed progenitors or preadipocytes. Human native progenitor cells CD34+/CD31-, contained in stroma vascular fraction (SVF), display adipogenic potential. However different cellular state markers are lacking. While white and brown AT were well studied in mice, a brite adipocyte was recently evinced in mice and human. More metabolically active than white, brite adipocytes exhibit features at the crossroads of brown and white adipocytes and could be a new target to fight against obesity associated pathologies. We propose to characterize heterogeneity of CD34+/CD31- to identify cell subsets in different states and/or with distinct white or brite fates. Heterogeneity of human CD34+/CD31- cells was studied by flow cytometry (n=54). In vitro experiments on native CD34+/CD31- were done to evaluate modifications on cell subsets ratio during adipogenesis (n=13). Cell sorting approaches were developped to isolate the progenitor subsets. Adipogenic potential of selected cell subsets was assessed in vitro (n=6). Cell subsets states and/or fates in terms of white or brite potentials were assessed by gene expression analyses (n=10). In vivo adipogenic potential of human progenitor subsets was assessed by cellular graft in NMRI mice. 6 weeks after graft, adipocyte formation was checked on implantation site (n=3).We identified 3 progenitor subsets in adult human native AT-SVF. The first one (P1) decreases with obesity. P1 is less represented in human visceral AT (VAT) than in subcutaneous AT (SAT). Furthermore this freshly harvested cell subset displays the highest expression of anti-adipogenic genes as KLF2. Finally P1 has the lowest adipogenic potential in vitro and in vivo. Inversly the second one identified (P2) increases with obesity. P2 is less present in VAT than in SAT. Expression of pro adipogenic genes is higher in P2 compared to P1: PPARγ2 (1.5 fold increase, p<0.05), CHREBP (2 fold increase, p<0.01), and PLIN1 (3 fold increase, p<0.01). P2 displays the better adipogenic potential in vitro and in vivo. P2 has a significant higher expression in brite/brown markers than P1 as CIDEA or TMEM26 (n=9, p<0.05). Mitochondria content, assessed using Mitotracker, is higher in P2 (n=6, p<0.01). The last one (P3) has an intermediate phenotype based on gene expression profile and on adipogenic potential in vitro and in vivo. Our data allow to identify 3 human progenitor subsets in CD34+/CD31- population in different states or with distinct fates. P2 appears as the most committed cell subset and probably contains the white and brite preadipocyte.



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