Abstract
Controversy surrounds the identity, origin, and physiologic role of endogenous cardiomyocyte progenitors in adult mammals. Using an inducible genetic labeling approach to identify small non-myocyte cells expressing cardiac markers, we find that activated endogenous cardioblasts are rarely evident in the normal adult mouse heart. However, myocardial infarction results in significant cardioblast activation at the site of injury. Genetically labeled isolated cardioblasts express cardiac transcription factors and sarcomeric proteins, exhibit spontaneous contractions, and form mature cardiomyocytes in vivo after injection into unlabeled recipient hearts. The activated cardioblasts do not arise from hematogenous seeding, cardiomyocyte dedifferentiation, or mere expansion of a preformed progenitor pool. Cell therapy with cardiosphere-derived cells amplifies innate cardioblast-mediated tissue regeneration, in part through the secretion of stromal cell-derived factor 1 by transplanted cells. Thus, stimulation of endogenous cardioblasts by exogenous cells mediates therapeutic regeneration of injured myocardium.
Highlights
The adult mammalian heart is viewed as a dynamic organ, capable of endogenous regeneration
Examination of the isolated cardiomyocytedepleted cell fraction revealed small (11.5 Æ 3.7 lm) round green fluorescent protein (GFP)+, lacZÀ cells which we go on to implicate as cardioblasts (Fig 1D, E and I)
These results demonstrate that MI results in cardioblast activation within the risk area
Summary
The adult mammalian heart is viewed as a dynamic organ, capable of endogenous regeneration. Improved insights into the cellular and molecular mechanisms of endogenous heart regeneration are needed, as the field is rife with controversy (Laflamme & Murry, 2011; Steinhauser & Lee, 2011; Garbern & Lee, 2013). While adult cardiomyocytes retain a detectable (albeit small) ability to proliferate (Soonpaa & Field, 1997; Malliaras et al, 2013a; Senyo et al, 2013), the role of endogenous progenitor cells in adult cardiomyogenesis is unclear (Laflamme & Murry, 2011; Steinhauser & Lee, 2011; Garbern & Lee, 2013; Koudstaal et al, 2013). The physiologic importance of these various progenitor populations and their contribution to cardiomyocyte replenishment in the normal or injured adult heart remain topics of intense debate
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