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Understanding the Molecular and Cellular Mechanisms of Cardiac Progenitor Cell Development
1. Non-Canonical Notch Signaling in CPC Development
Notch1-deficiency in CPCs leads to a marked expansion of CPCs with increased proliferation by negatively regulating active ß-Catenin, the downstream effector of the Wnt pathway. The CPC expansion occurs independent of the transcriptional mediator of canonical Notch signaling, RBP-J, suggesting that Notch1 regulates CPC expansion by a non-canonical pathway. We are investigating a novel role of Notch signaling independent of its ligand-induced transcriptional activity in regulation of CPCs and ß-Catenin.
2. Isl1 and Wnt Regulation of CPC Development
Wnt/ß-Catenin signaling promotes CPC expansion. Islet1, a central regulator of cardiogenesis that transiently marks undifferentiated CPCs, may be an important mediator of Wnt/ß-Catenin signaling affecting CPC proliferation or differentiation.
To understand how cellular decisions are implemented by Islet1 and Wnt/ß-catenin signaling, we are investigating the critical downstream pathways that affect CPC maintenance and differentiation.
3. Induction and Lineage-Specific Differentiation of Cardiac Progenitors
How does the induction of pre-cardiac mesoderm occur? ESCs, derived from the inner cell mass of the blastocyst, differentiate into the three germ layers, endoderm, mesoderm and ectoderm, and their derivatives. CPCs are selected in a subset of mesoderm and further differentiate into diverse cardiac cell types. We are investigating the mechanisms by which the pre-cardiac field is induced and selected from the early mesoderm and CPCs are directed to differentiate into specific cardiac cell types.
We have developed several novel approaches to dissect the mechanisms regulating CPC development, including the use of embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) and mouse models for the analysis. View a video of a beating cardiomyocyte sheet.