Location: Arkansas Children's Nutrition CenterTitle: Distinct adipogenic differentiation phenotypes of human umbilical cord mesenchymal cells dependent on adipogenic conditions
|SABEN, JESSICA - Arkansas Children'S Nutrition Research Center (ACNC)|
|THAKALI, KESHARI - Arkansas Children'S Nutrition Research Center (ACNC)|
|LINDSEY, FORREST - Arkansas Children'S Nutrition Research Center (ACNC)|
|ZHONG, YING - Arkansas Children'S Nutrition Research Center (ACNC)|
|Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)|
|ANDRES, ALINE - Arkansas Children'S Nutrition Research Center (ACNC)|
|SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: Experimental Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2014
Publication Date: 10/1/2015
Citation: Saben, J., Thakali, K.M., Lindsey, F.E., Zhong, Y., Badger, T.M., Andres, A., Shankar, K. 2015. Distinct adipogenic differentiation phenotypes of human umbilical cord mesenchymal cells dependent on adipogenic conditions. Experimental Biology and Medicine. 239(10):1340-1351.
Interpretive Summary: Aberrant expansion of adipose tissue is central to obesity and other metabolic disorders, including type 2 diabetes. The process of cellular differentiation into adipocytes (viz. adipogenesis) has been extensively studied in murine cell lines. Umbilical cord matrix derived stem cells (UCMSCs) provide a relatively accessible human in vitro system to study adipogenesis, and as a source of fetal stem cells, can be used to test the effects of the in utero environment on persistent effects in the offspring. In the present study, we studied the differentiation potential of cells isolated from cord tissue of healthy infants. These studies demonstrate that cells from cord tissue effectively transform into fat cells under adipogenic stimuli and recapitulate many functional characteristics of fat cells. These studies uncover fundamental aspects of UCMSC differentiation capacity towards the adipocytic lineage.
Technical Abstract: The umbilical cord (UC) matrix is a source of multipotent mesenchymal stem cells (MSCs) that have adipogenic potential and thus can be a model to study adipogenesis. However, existing variability in adipocytic differentiation outcomes may be due to discrepancies in methods utilized for adipogenic differentiation. Additionally, functional characterization of UCMSCs as adipocytes has not been described. We tested the potential of three well-established adipogenic cocktails containing IBMX, dexamethasone, and insulin (MDI) plus indomethacin (MDI-I) or rosiglitazone (MDI-R) to stimulate adipocyte differentiation in UCMSCs. MDI, MDI-I, and MDI-R treatment significantly increased PPAR gamma and C/EBP alpha'mRNA and induced lipid droplet formation. However, MDI-I had the greatest impact on mRNA expressions of PPAR gamma, C/EBP alpha, FABP4, GPD1, PLIN1, PLIN2, and ADIPOQ, and lipid accumulation, whereas MDI showed the least. Interestingly, there were no treatment group differences in the amount of PPAR gamma protein. However, MDI-I treated cells had significantly more C/EBP alpha protein compared to MDI or MDI-R, suggesting that indomethacin-dependent increased C/EBP alpha'may contribute to the adipogenesis-inducing potency of MDI-I. Additionally, BMP4 treatment of UC-MSCs did not enhance responsiveness to MDI-induced differentiation. Finally to characterize adipocyte function, differentiated UCMSCs were stimulated with insulin and downstream insulin signaling was measured. Differentiated UCMSCs were responsive at two weeks but showed decreased sensitivity by five weeks of differentiation, suggesting that long-term differentiation may induce insulin resistance. Together, these data indicate that UCMSCs undergo adipogenesis when differentiated in MDI, MDI-I, MDI-R; however, the presence of indomethacin greatly enhances their adipogenic potential. Furthermore, our results suggest that insulin signaling pathways of differentiated UCMSCs are functionally similar to adipocytes.