Stem Cells Dev. 2017 Sep 6. doi: 10.1089/scd.2017.0071. [Epub ahead of print]

The Role of Cellular Proliferation in Adipogenic Differentiation of Human Mesenchymal Stem Cells.

Marquez M^1,2, Alencastro F^3,4, Madrigal A^1,5, Jiminez J^3,6, Blanco G^1,7, Gureghian A⁸, Keagy L⁹, Lee C¹⁰, Liu R¹¹, Tan L¹², Deign K¹³, Armstrong B¹⁴, Zhao Y¹⁵.

Abstract

Mitotic clonal expansion has been suggested as a pre-requisite for adipogenesis in murine preadipocytes, but the precise role of cell proliferation during human adipogenesis is unclear. Using adipose tissue derived human mesenchymal stem cells as an in vitro cell model for adipogenic study, a group of cell cycle regulators including Cdk1 and CCND1 were found to be down-regulated as early as 24 hours post adipogenic initiation and consistently, cell proliferation activity was restricted to the first 48 hours of adipogenic induction. Cell proliferation was either further inhibited using siRNAs targeting cell cycle genes or enhanced by supplementing exogenous growth factor bFGF at specific time intervals during adipogenesis. Expression knock-down of Cdk1 at the initiation of adipogenic induction resulted in significantly increased adipocytes even though total number of cells were significantly reduced as compared to siControl treated cells. BFGF stimulated proliferation throughout adipogenic differentiation but exerted differential effect on adipogenic outcome at different phases, promoting adipogenesis during mitotic phase (first 48 hours) but significantly inhibiting adipogenesis during adipogenic commitment phase (days 3-6). Our results demonstrate that cellular proliferation is counteractive to adipogenic commitment in human adipogenesis. However, cellular proliferation stimulation can be beneficial for adipogenesis during the mitotic phase by increasing the population of cells capable of committing to adipocytes before adipogenic commitment.