Cardiac Stem Cells

Mammalian heart demonstrates a low repair capacity, mainly involved in the physiological maintainment of the organ. In any case, the intimate responsible mechanisms still continue being a matter of controversy. BMI1 plays a central role in many of the well-characterized adult stem cell compartments, favoring self-renewal of primitive stem cells (SC) and regulating their differentiation. Our central working hypothesis focuses into the demonstration of a similar role for Bmi1 in putative cardiac stem cells (CSCs).

By lineage tracing analysis we have demonstrated that the adult mouse heart has a minoritarian non-cardiomyocytic population that expresses high levels of Bmi1. This population, that we denominate B-CPC (for Bmi1+ Cardiac Progenitor Cells), shows a a gene expression profile characteristic of immature or stem cells, and contributes to the physiological turnover of cardiomyocytes (CM), with an stimated annual rate of 2-6%. In addition, results indicate that B-CPC is an heterogeneous population that could include cells with a long-term SC profile and progenitors (short-term), for an efficient immediate response. Currently, we pretend to consolidate and get a deeper comprehesion of this  concept, aiming to contribute to the current installed confussion in the field.

We plan to will go deeper in the characterization and regulation mechanism of the B-CPC compartment, including: a) validation of RNAseq results; b) quantitative analysis of the contribution of B-CPC progeny to endothelial, smooth muscle and fibroblastic cell lineages; and c) analysis of damage response capacity: acute myocardial infarct (AMI), oxidative damage and irradiation. Additionally, we consider relevant to study in deep the B-CPC subpopulations proposed: Bmi1high (H) y Bmi1low (L); we propose to carry out and important study trying to demonstrate whether those subpopulations could be associated to the proposed SC-long-term and SC-short-term profile, respectively. Finally, we initiate the in vivo study of two genes (Mbd3 y miR-300) that we have defined as relevant for the regulation of B-CPC compartment. To facilitate the propose reseach we have obtained, and currently  is under characterization, a conditionally immortalized cell line, derived from B-CPC, that would be an unvaluable tool for a priori screening of complex combination of variables or preliminar evaluation of gain- or loss of functions manipulations, prior to address costly (both in money and effort terms) work with primary cells and animal models.