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.
Highlights
The mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life
Pulse-chase analysis showed that B-Cardiac progenitor cells (CPC) remained quite stable for extended periods, which suggests that this Bmi1+ population contains cardiac progenitors with substantial self-maintenance potential
High 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
Summary
The mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life. Adult resident cardiac stem/progenitors are defined primarily by the expression of cell surface markers such as c-KIT [8], SCA-1 [9, 10], ATP-binding cassette ABCG2 [11], PDGFRα [12] or combinations of Valiente-Alandi et al Stem Cell Research & Therapy (2015) 6:205 these The diversity of these findings has hindered a broad, unambiguous consensus for identification and molecular definition of endogenous CSC [3]. A cardiac progenitor population defined as TIE-1+ CPC, a classical endothelial marker, is able to generate 70 % of the SCA-1+ intermediate perivascular progenitors that contribute (up to 3 %) to CM homeostatic turnover origin [19] These findings reinforce the hypothesis that cardiac progenitor cells support the low CM turnover in the adult heart. Further genetic lineage tracing studies will help to elucidate the complex relationship between these partially different populations
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