Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long
Isabelle Plaisance1, Stéphanie Perruchoud1, Miguel Fernandez-Tenorio2
1Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
Abstract:
The mechanisms controlling differentiation in adult cardiac precursor cells (CPCs) are still largely unknown. In this study, CPCs isolated from the human heart were found to produce predominantly smooth muscle cells but could be redirected to the cardiomyocyte fate by transient activation followed by inhibition of NOTCH signaling. NOTCH inhibition repressed MIR-143/145 expression, and blocked smooth muscle differentiation. Expression of the microRNAs is under control of CARMEN, a long noncoding RNA associated with an enhancer located in the MIR-143/145 locus and target of NOTCH signaling. The CARMEN/MIR-145/143 axis represents, therefore, a promising target to favor production of cardiomyocytes in cell replacement therapies.
Insights
Researchers found that inhibiting NOTCH signaling in human cardiac precursor cells (CPCs) redirects them to become cardiomyocytes. This NOTCH inhibition impacts the CARMEN/MIR-143/145 axis, offering a new target for cardiac cell replacement therapies.
Area of Science:
- Cardiovascular Biology
- Stem Cell Differentiation
- Molecular Mechanisms
Background:
- Mechanisms governing adult cardiac precursor cell (CPC) differentiation remain poorly understood.
- CPCs typically differentiate into smooth muscle cells, limiting their therapeutic potential for heart repair.
Purpose of the Study:
- To investigate methods for redirecting CPC differentiation towards cardiomyocytes.
- To identify molecular pathways controlling CPC fate decisions.
Main Methods:
- Isolation and culture of human cardiac precursor cells (CPCs).
- Manipulation of NOTCH signaling pathways (activation followed by inhibition).
- Analysis of microRNA (MIR-143/145) and long noncoding RNA (CARMEN) expression.
Main Results:
- Transient NOTCH activation followed by inhibition successfully redirected CPCs to a cardiomyocyte fate.
- NOTCH inhibition suppressed MIR-143/145 expression, blocking smooth muscle differentiation.
- The CARMEN long noncoding RNA, regulated by NOTCH signaling, controls MIR-143/145 expression.
Conclusions:
- The CARMEN/MIR-143/145 axis is a key regulator of CPC differentiation.
- Targeting this axis offers a novel strategy to enhance cardiomyocyte production for cell replacement therapies in cardiac conditions.
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