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C-kitCre Knock-ins Fail to Identify, Effectively Recombine and Fate-Map Cardiac Stem Cells

ABSTRACT: A recent cell-fate mapping study by Van Berlo et al. using a Cre knock-in (KI) into the c-kit locus, and two other studies using a similar genetic approach to track the fate of Cardiac Stem/progenitor Cells (CSCs) concluded that c-kitpos cells only negligibly generate cardiomyocytes. These papers questioned our findings that tissue-specific c-kitposCSCs are endogenous regenerative agents necessary and sufficient for cardiomyocyte regeneration/replenishment after injury. We consider answering whether the c-kitCre-KI approach properly identifies and fate-maps c-kitposCSCs and/or whether c-kitCre-KI-insertion affects CSC biology and cardiomyogenic potential. To test this hypothesis, we crossed the the c-kitCre-KI mouse to different reporter mouse models. We concluded that the c-kitCre-KI approach neither identifies nor fate-tracks the c-kitposCSCs, because c-kit expression level in these cells is too low to produce enough Cre to effectively recombine the floxed marker and permanently tag the CSC and their progeny.

ORGANISM(S): Mus musculus

PROVIDER: GSE102002 | GEO | 2018/03/23

REPOSITORIES: GEO

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Project description:Multipotent adult resident cardiac stem cells (CSCs) originally were identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone distinguish CSCs from other c-kit-expressing cardiac cells because the adult heart contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has not been considered in recent c-kit-expressing cell fate mapping publications, which have equated the contribution of the whole heterogeneous c-kitpos population to cardiomyocyte generation in adulthood, which is minimal, to that of the CSCs, a result at odds with previous publications. To shed light on this issue, we have assessed the identity, abundancy and myogenic potential of true multipotent CSCs within the total c-kitpos cardiac cell cohort. Blood lineage-committed c-kitpos cells were removed by CD45 negative sorting to obtain a CD45negc-kitpos cell population (<10% of the total c-kitpos cells), which is enriched for cells that express c-kit at low levels and possess all properties of multipotent stem/progenitor cells in vitro. These characteristics are absent from the c-kitneg and the lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived CSC clones, representing 1-2% of total c-kitpos cells, when instructed by TGF-b/Wnt molecules, acquire full transcriptome expression, sarcomere organization, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes. Significantly, clonogenic CSCs have a potent cardio-regenerative/repair capacity in vivo after acute myocardial infarction. CSC myogenic regenerative capacity is dependent on cardiomyocyte commitment through activation of the SMAD2 pathway. Such regeneration was not apparent when freshly-isolated total c-kitpos cardiac cells were administered. In conclusion, only a very small fraction of cardiac c-kitpos cells (~1-2%) have the characteristics of multipotent CSCs but these exhibit robust myogenic properties.  

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C-kitCre Knock-ins Fail to Identify, Effectively Recombine and Fate-Map Cardiac Stem Cells

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