Developmental Origin of Postnatal Cardiomyogenic Progenitor Cells

Abstract

Aim: To trace the cell origin of the cells involved in postnatal cardiomyogenesis. Materials & methods: Nkx2.5 enhancer-eGFP (Nkx2.5 enh-eGFP) mice were used to test the cardiomyogenic potential of Nkx2.5 enhancer-expressing cells. By analyzing Cre excision of activated Nkx2.5-eGFP+ cells from different lineage-Cre/Nkx2.5 enh-eGFP/ROSA26 reporter mice, we traced the developmental origin of Nkx2.5 enhancer-expressing cells. Results: Nkx2.5 enhancer-expressing cells could differentiate into striated cardiomyocytes both in vitro and in vivo. Nkx2.5-eGFP+ cells increased remarkably after experimental myocardial infarction (MI). The post-MI Nkx2.5-eGFP+ cells originated from the embryonic epicardial cells, not from the pre-existing cardiomyocytes, endothelial cells, cardiac neural crest cells or perinatal/postnatal epicardial cells. Conclusion: Postnatal Nkx2.5 enhancer-expressing cells are cardiomyogenic progenitor cells and originate from embryonic epicardium-derived cells.

Lay abstract: Recent studies report that postnatal mammalian hearts undergo cardiomyocyte refreshment; however, evidence is lacking for the cell origin of the cells involved in postnatal cardiomyogenesis. In this study, we confirmed that Nkx2.5 cardiac progenitor cells existed in the postnatal mouse heart and could differentiate into striated cardiomyocytes both in vitro and in vivo. The developmental origin of these postnatal Nkx2.5 cardiac progenitor cells are from the embryonic epicardial cells.

Keywords::

• cardiac regeneration
• cardiac progenitor cells
• Nkx2.5
• myocardial infarction
• epicardium-derived cells

Acknowledgements

The authors would like to thank S Wu at Stanford University School of Medicine for the Nk2.5 enh-eGFP mice.

Financial & competing interests disclosure

This study was supported by grants of Far Eastern Memorial Hospital (FEMH 98–2314-B-418-004-MY2, FEMH-98-SCRM-B-002, FEMH-99-SCRM-A-005, FEMH-2011-SCRM-A-007, FEMH-2013-C-024, FEMH-2013-SCRM-A-004, FEMH-2014-SCRM-007, FEMH-2014-C-029, FEMH-2015-C-010), Far Eastern Memorial Hospital National Taiwan University Hospital Joint Research Program (99-FTN05, 100-FTN03, 101-FTN12, 102-FTN05, 103-FTN06), and the National Scientific Council (NSC 98-2314-B-418–004-MY2). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Author contributions

Yuan-Hung Liu designed study, performed animal experiments, evaluated most of data, and wrote most of the manuscript. Ling-Ping Lai designed study. Shih-Yun Huang performed laboratory experiments. Yi-Shuan Lin performed laboratory experiments and manipulated animals. Shinn-Chih Wu designed animal studies. Chih-Jen Chou designed animal studies and manipulated animal studies. Jiunn-Lee Lin designed study and organized the team.