Faculty Collaboration Database

Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores. Stem Cells Transl Med 2017 Apr;6(4):1191-1201

Date

02/23/2017

Pubmed ID

28224719

Pubmed Central ID

PMC5442850

DOI

10.1002/sctm.16-0151

Scopus ID

2-s2.0-85017570513 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

To address concerns regarding the tumorigenic potential of undifferentiated human pluripotent stem cells (hPSC) that may remain after in vitro differentiation and ultimately limit the broad use of hPSC-derivatives for therapeutics, we recently described a method to selectively eliminate tumorigenic hPSC from their progeny by inhibiting nicotinamide phosphoribosyltransferase (NAMPT). Limited exposure to NAMPT inhibitors selectively removes hPSC from hPSC-derived cardiomyocytes (hPSC-CM) and spares a wide range of differentiated cell types; yet, it remains unclear when and how cells acquire resistance to NAMPT inhibition during differentiation. In this study, we examined the effects of NAMPT inhibition among multiple time points of cardiomyocyte differentiation. Overall, these studies show that in vitro cardiomyogenic commitment and continued culturing provides resistance to NAMPT inhibition and cell survival is associated with the ability to maintain cellular ATP pools despite depletion of NAD levels. Unlike cells at earlier stages of differentiation, day 28 hPSC-CM can survive longer periods of NAMPT inhibition and maintain ATP generation by glycolysis and/or mitochondrial respiration. This is distinct from terminally differentiated fibroblasts, which maintain mitochondrial respiration during NAMPT inhibition. Overall, these results provide new mechanistic insight into how regulation of cellular NAD and energy pools change with hPSC-CM differentiation and further inform how NAMPT inhibition strategies could be implemented within the context of cardiomyocyte differentiation. Stem Cells Translational Medicine 2017;6:1191-1201.

Author List

Kropp EM, Broniowska KA, Waas M, Nycz A, Corbett JA, Gundry RL

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acrylamides
Cell Differentiation
Cell Survival
Cells, Cultured
Enzyme Inhibitors
Humans
Myocytes, Cardiac
Nicotinamide Phosphoribosyltransferase
Piperidines
Pluripotent Stem Cells