Abstract 15243: Limited Gene Expression Profile in Induced Pluripotent Stem Cells Predicts Cardiogenic Outcome Across Diverse Somatic Cell Origins
The cardiogenic capacity of induced pluripotent stem cells (iPSCs) has been harnessed for diagnostic and therapeutic applications that are transforming the field of cardiovascular regenerative medicine. Innovative disease-modeling studies rely on comparisons between patient-specific iPSCs and healthy controls. However, the propensity of iPSCs to undergo cardiac differentiation is highly variable across iPSC lines, even from the same individual. Unpredictable clonal heterogeneity as well as residual influence of the somatic origin and reprogramming strategy can variegate iPSC cardiogenicity and may confound health versus disease comparisons.
This study aimed to generate and characterize over 60 iPSC lines derived from different somatic sources and reprogramming strategies in order to (1) determine if source or strategy has greater influence on cardiogenicity and (2) develop a predictive selection criterion to decrease clonal variability and select iPSCs with consistent cardiogenic output.
Histological and cellular pluripotency criteria were indistinguishable across iPSC lines, whereas a transcriptional profile of pluripotent genes could selectively eliminate outlier iPSCs that were distinct from mouse embryonic stem cells (mESCs). This pluripotency screen was then applied to iPSCs derived from unique fibroblast origins (embryonic, cardiac, or tail tip) via distinct nuclear reprogramming strategies (random viral integration or drug-induced transgene expression). Notably, reprogramming strategy showed a greater influence on cardiogenic capacity than did somatic origin. Reactivation as well as higher baseline expression of pluripotency genes was correlated with decreased cardiogenicity in iPSCs derived from lentiviral reprogramming. In addition, a cardiogenic predictor was established to identify highly cardiogenic iPSC lines across somatic origins and reprogramming strategies.
This study demonstrates (1) that the degree of somatic origin influence on iPSC cardiogenicity varies across reprogramming strategies and (2) that baseline pluripotency gene expression can be utilized to select mESC-like iPSCs and harnessed as a predictor of iPSCs with consistent cardiogenic output.
- © 2013 by American Heart Association, Inc.