Endogenous resident c-Kit cardiac stem cells increase in mice with an exercise-induced, physiologically hypertrophied heart

Abstract

Physical activity evokes well-known adaptations in the cardiovascular system. Although exercise training induces cardiac remodeling, whether multipotent stem cells play a functional role in the hypertrophic process remains unknown. To evaluate this possibility, C57BL/6 mice were subjected to swimming training aimed at achieving cardiac hypertrophy, which was morphologically and electrocardiographically characterized. Subsequently, c-Kit(+)Lin(-) and Sca-1(+)Lin(-) cardiac stem cells (CSCs) were quantified using flow cytometry while cardiac muscle-derived stromal cells (CMSCs, also known as cardiac-derived mesenchymal stem cells) were assessed using in vitro colony-forming unit fibroblast assay (CFU-F). Only the number of c-Kit(+)Lin(-) cells increased in the hypertrophied heart. To investigate a possible extracardiac origin of these cells, a parabiotic eGFP transgenic/wild-type mouse model was used. The parabiotic pairs were subjected to swimming, and the wild-type heart in particular was tested for eGFP(+) stem cells. The results revealed a negligible number of extracardiac stem cells in the heart, allowing us to infer a cardiac origin for the increased amount of detected c-Kit(+) cells. In conclusion, the number of resident Sca-1(+)Lin(-) cells and CMSCs was not changed, whereas the number of c-Kit(+)Lin(-) cells was increased during physiological cardiac hypertrophy. These c-Kit(+)Lin(-) CSCs may contribute to the physiological cardiac remodeling that result from exercise training.

Muscle stem cell and physical activity: what point is the debate at?

“…Although the principal player of cardiac hypertrophy is the enlargement of differentiated cardiomyocytes, Leite et al [102] recently demonstrated that also c-kit + cardiac stem cells (CSC) participate to cardiac hypertrophy generated by physical exercise. c-Kit + CSC have been first reviewed 10 years ago [103].…”

Pathological Left Ventricular Hypertrophy and Stem Cells: Current Evidence and New Perspectives

“…CSCs include, among others, c-kit + Lin − and Sca-1 + -Lin − cells, Isl-1 progenitors, epicardial progenitors, and progenitors generating cardiospheres and muscle-derived mesenchymal stem cells. Experimental studies have shown that it is mostly c-kit + Lin − cells that seem to increase in the heart in response to exercise training [ 5 ]. However, it has been speculated that Sca-1 + -Lin − might also be stimulated in physiological hypertrophy.…”

Telocytes in exercise‐induced cardiac growth

“…These newly formed cardiomyocytes could be either from pre‐existing cardiomyocytes or from cardiac progenitor/stem cells, which needs to be further clarified by myocyte‐restricted lineage tracing experiments . Exercise has been reported to activate cardiac stem cells while mammalian heart renewal has been supposed to be mainly mediated by pre‐existing cardiomyocytes . Despite the unravelled cell source of these newly formed cardiomyocytes, understanding the molecular and cellular mechanisms of exercise‐induced cardiac growth might provide novel strategies to enhance the limited endogenous capacity for cardiac regeneration .…”