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Evidence for minimal cardiogenic potential of Sca-1 positive cells in the adult mouse heart

By Lauren E. Neidig, Florian Weinberger, Nathan J. Palpant, John Mignone, Amy M. Martinson, Daniel W. Sorensen, Ingrid Bender, Natsumi Nemoto, Hans Reinecke, Lil Pabon, Jeffery Molkentin, Charles E Murry, Jop H. van Berlo

Posted 29 Aug 2018
bioRxiv DOI: 10.1101/404038

Background: Despite modern pharmacotherapy, heart failure remains a major medical burden. The heart has a limited regenerative capacity, and bolstering regeneration might represent new therapeutic approaches for heart failure patients. Various progenitor cells in the heart have been proposed to have cardiomyogenic properties, but this evidence is based mostly on cell culture and transplantation studies. One population of interest is characterized by the expression of Stem Cell Antigen-1 (Sca-1). Here we tested the hypothesis that Sca-1+ cells are endogenous progenitors for cardiomyocytes in the adult heart. Methods: We evaluated the innate cardiogenic potential of Sca-1+ cells in vivo by generating a novel mouse model to genetically lineage-trace the fate of Sca-1 expressing cells. This was accomplished by introducing a tamoxifen-inducible Cre-recombinase into the Sca-1 locus (Sca-1mCm/+). Crossing this mouse line to a Cre-dependent tdTomato reporter line allowed for genetic lineage-tracing of endogenous Sca-1+ cells (Sca-1mCmR26tdTomato). The frequency of Sca-1+ cardiomyocytes was quantified from dispersed cell preparations and confirmed by in situ histology. Results: We validated the genetic lineage tracing mouse model in bone marrow and heart. Unlike previous publications suggesting significant cardiogenic potential, we found that less than 0.02% of cardiomyocytes per year were derived from Sca-1+ cells in the adult heart under homeostatic conditions. At six months after myocardial infarction, we found less than 0.01% of cardiomyocytes were derived from Sca-1+ cells. Conclusion: Our results show that Sca-1+ cells in the adult heart have minimal cardiogenic potential under homeostatic conditions or in response to myocardial infarction.

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