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Understanding the Molecular and Cellular Mechanisms of Cardiac Progenitor Cell Development

Ongoing Research

Multipotent cardiac progenitor cells can be isolated from early embryos.
Multipotent cardiac progenitor cells (CPCs) can be isolated from early embryos or differentiating embryonic stem cells
(ESCs) and cultured to differentiate into numerous cardiac cell types. Our research goal is to elucidate the molecular
and cellular mechanisms underlying self-renewal and differentiation of CPCs.

1. Non-Canonical Notch Signaling in CPC Development

Notch1 Deficiency Promotes CPC Expansion
Notch1 Deficiency Promotes CPC Expansion. A-D,
Transverse sections of indicated embryos focused on
CPCs (asterisk, A, B) or standed with Isl1 antibodies
(green) and dapi (blue) (C, D). ot, outflow tract

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/Beta-Catenin signals promote CPC expansion, resulting in heart enlargement.
Wnt/ß-Catenin signals promote CPC expansion,
resulting in heart enlargement. H, heart.

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.

Approaches

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.


 

 
 

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