c-kit ⁺ precursors support postinfarction myogenesis in the neonatal, but not adult, heart

Abstract

We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit + cardiovascular precursor cells (CPC) that are known to be present in early heart development. Infarction of postnatal day 1–3 c-kit BAC -EGFP mouse hearts induced the localized expansion of (c-kit)EGFP + cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP + cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP + cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to scid mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP + /(αMHC)mCherry − (noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP + myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.

Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family

“…However, no fate mapping studies have been performed to date to examine this possibility. Although a recent report showed activation of a c-kit reporter after myocardial cryoinjury in the neonate (18), it is difficult to reach a conclusion about some minor role of progenitor cells in neonatal heart regeneration without carefully designed fate mapping studies. Although c-kit is expressed in a subset of cardiac progenitor cells, it is known that c-kit is also expressed during cardiomyocyte dedifferentiation (19,20), and proliferation (21), which are known features of the neonatal cardiac regenerative response.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…However, KIT is not a unique marker of this proposed cardiac stem cell population. KIT expression has been reported in postnatal cardiomyocytes , in adult cardiomyocytes induced to dedifferentiate (Jesty et al, 2012;Kubin et al, 2011;Zhang et al, 2010), as well as in coronary endothelial cells and epicardial cells (Castaldo et al, 2008;Limana et al, 2007;Tallini et al, 2009). KIT expression can also be induced from KIT − cells in vitro (Keith and Bolli, 2015).…”

“…The authors concluded that differentiated EGFP + cells could not have arisen by self-renewal or division of stem cells. A subsequent study suggested that cells carrying the same reporter construct could in fact form some new cardiomyocytes and vascular cells in cryo-injured neonatal hearts; however, in injured adult hearts only vascular cells formed (Jesty et al, 2012). It is important to note that these studies are limited by the indirect nature of the lineagetracing methods.…”

Sensory hair cell development and regeneration: similarities and differences

“…For example, in the immature heart and lungs of neonatal mice, injury is met with a robust degree of regeneration/ repair, but this phenomenon decreases with age (Jesty et al, 2012;Paxson et al, 2011;Porrello et al, 2011). Neural stem cells also decrease in number as the animal ages (Maslov et al, 2004), and this decrease in the stem cell reserve is implicated in the decline in tissue repair seen with aging (Jin et al, 2004).…”