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

Stem Cell Research & Therapy

Antonio Bernad²  Mario Capecchi⁶  José C. Segovia⁴  Maria Garcia-Gomez⁴  Elvira Arza¹  Diego Herrero²  Carmen Albo-Castellanos³  Iñigo Valiente-Alandi⁵ 

[1] Microscopy Unit, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain;Immunology and Oncology Department, Spanish National Center for Biotechnology (CNB-CSIC), Madrid, Spain;Vivebiotech, San Sebastian, Spain;Advanced Therapies Mixed Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain;The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Howard Hughes Medical Institute University of Utah, Salt Lake City, UT, USA

关键词: Cardiac progenitor cells;    Bmi1;    Stem cells;    Heart homeostasis;   

Others  :  1234420
DOI  :  10.1186/s13287-015-0196-9

 received in 2015-07-16, accepted in 2015-10-02,  发布年份 2015

【 摘 要 】

Introduction

The 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.

Methods

Bmi1^CreER/+ ;Rosa26^YFP/+(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.

Results

FACS 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.

Conclusions

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.

【 授权许可】

   
2015 Valiente-Alandi et al.

【 图 表 】

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