Cardiac Bmi1 + cells contribute to myocardial renewal in the murine adult heart

Abstract

IntroductionThe mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life. Although many cardiac stem cell populations have been studied, the natural source for homeostatic repair has not yet been defined. The Polycomb protein BMI1 is the most representative marker of mouse adult stem cell systems. We have evaluated the relevance and role of cardiac Bmi1+ cells in cardiac physiological homeostasis.MethodsBmi1CreER/+;Rosa26YFP/+ (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1+ cells. These cells and their progeny were tracked by FACS, immunofluorescence and RT-qPCR techniques from 5 days to 1 year.ResultsFACS analysis of non-cardiomyocyte compartment from TM-induced Bmi1-YFP mice showed a Bmi1+-expressing cardiac progenitor cell (Bmi1-CPC: B-CPC) population, SCA-1 antigen-positive (95.9 ± 0.4 %) that expresses some stemness-associated genes. B-CPC were also able to differentiate in vitro to the three main cardiac lineages. Pulse-chase analysis showed that B-CPC remained quite stable for extended periods (up to 1 year), which suggests that this Bmi1+ population contains cardiac progenitors with substantial self-maintenance potential. Specific immunostaining of Bmi1-YFP hearts serial sections 5 days post-TM induction indicated broad distribution of B-CPC, which were detected in variably sized clusters, although no YFP+ cardiomyocytes (CM) were detected at this time. Between 2 to 12 months after TM induction, YFP+ CM were clearly identified (3 ± 0.6 % to 6.7 ± 1.3 %) by immunohistochemistry of serial sections and by flow cytometry of total freshly isolated CM. B-CPC also contributed to endothelial and smooth muscle (SM) lineages in vivo.ConclusionsHigh Bmi1 expression identifies a non-cardiomyocyte resident cardiac population (B-CPC) that contributes to the main lineages of the heart in vitro and in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0196-9) contains supplementary material, which is available to authorized users.

Bmi‐1 high‐expressing cells enrich cardiac stem/progenitor cells and respond to heart injury

“…Agreed with our findings, Valiente‐Alandi I et al has crossed the Bmi‐1 CreER/+ strain with Rosa26 YFP/+ reporter mice to generate Bmi‐1 CreER/+ ;Rosa26 YFP/+ (Bmi‐1‐YFP) mice for cardiac lineage tracing, and demonstrated that Bmi‐1 + cells contribute to myocardial renewal and myocardial repair following acute injury . Furthermore, Bmi‐1 expression is associated with reactive oxygen species levels .…”

Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation

“…including those in the heart. [19] BMI1 acts as an epigenetic repressor, remodeling chromatin through histone monoubiquitination [20] Among its main targets, PCR1 represses Hox, p16 INK4a and master differentiation genes [21,22]. Additional PCR1 functions are described in mammalian somatic cells; BMI1 is needed for constitutive heterochromatin formation [23] and is recruited to DNA breaks after DNA damage [24].…”

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate

“…1H, histogram), when the mature endothelial and SMC differentiation occurs. Expression of bmi1, a member of the Polycomb repressive complex 1 and a known stem cell self-renewal marker [28,29], was increased by PK2 treatment of hEPDCs ( Fig. 1I).…”