Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart

Konstantinos Malliaras,Ke Cheng,Giselle Galang,Eduardo Marbán,Baiming Sun,Eleni Tseliou,Jeffrey Seinfeld,Yiqiang Zhang,Mohammad Aminzadeh

doi:10.1002/emmm.201201737

Abstract

Cardiosphere-derived cells (CDCs) have been shown to regenerate infarcted myocardium in patients after myocardial infarction (MI). However, whether the cells of the newly formed myocardium originate from the proliferation of adult cardiomyocytes or from the differentiation of endogenous stem cells remains unknown. Using genetic fate mapping to mark resident myocytes in combination with long-term BrdU pulsing, we investigated the origins of postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mammalian heart. In the normal mouse heart, cardiomyocyte turnover occurs predominantly through proliferation of resident cardiomyocytes at a rate of ∼1.3–4%/year. After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes. Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium. The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair. Thus, CDCs induce myocardial regeneration by differentially upregulating two mechanisms of endogenous cell proliferation.

Highlights

The concept of the adult mammalian heart as a dynamic organ capable of limited endogenous regeneration has been convincingly established (Bergmann et al, 2009)
After 14 days of daily 4-OH-Tamoxifen administration [which resulted in a 79.2% (Æ7.1%) labelling efficiency of cardiomyocytes (Supporting Information Fig 1C), confirming previous reports (Hsieh et al, 2007; Loffredo et al, 2011)], 6–8 week old bitransgenic MerCreMer/ZEG mice were randomly assigned to three groups: (a) sham surgery; (b) induction of myocardial infarction (MI) by permanent ligation of the left anterior coronary artery (LAD); (c) induction of MI followed by intramyocardial injection of mouse Cardiosphere-derived cells (CDCs) (2 Â 105, grown from wild-type animals) into the infarct border zone
This finding is in agreement with two recently published studies: one showing that cell therapy can indirectly increase the contribution of host progenitors to the myocyte pool (Loffredo et al, 2011) and another showing that therapeutic exploitation of the combination of enhanced stem cell recruitment and cardiomyocyte cell cycle induction results in increased myocardial renewal after MI (Zaruba et al, 2012)

Summary

Introduction

The concept of the adult mammalian heart as a dynamic organ capable of limited endogenous regeneration has been convincingly established (Bergmann et al, 2009). Estimated rates of turnover vary wildly (Kajstura et al, 2010) and the underlying cellular mechanisms remain unclear (Laflamme & Murry, 2011; Steinhauser & Lee, 2011). It is still unknown whether the adult mammalian heart generates new cardiomyocytes through myogenic differentiation of endogenous stem cells [as has been described in the normal (Hosoda et al, 2009), Cardiosphere-derived cells (CDCs) (Smith et al, 2007) have been shown to regenerate functional heart muscle in patients post-myocardial infarction (MI) in the recently reported CADUCEUS study (Makkar et al, 2012).

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Conclusion