Abstract
The mammalian target of rapamycin (mTOR) signaling pathway efficiently regulates the energy state of cells and maintains tissue homeostasis. Dysregulation of the mTOR pathway has been implicated in several human diseases. Rapamycin is a specific inhibitor of mTOR and pharmacological inhibition of mTOR with rapamycin promote cardiac cell generation from the differentiation of mouse and human embryonic stem cells. These studies strongly implicate a role of sustained mTOR activity in the differentiating functions of embryonic stem cells; however, they do not directly address the required effect for sustained mTOR activity in human cardiac progenitor cells. In the present study, we evaluated the effect of mTOR inhibition by rapamycin on the cellular function of human cardiac progenitor cells and discovered that treatment with rapamycin markedly attenuated replicative cell senescence in human cardiac progenitor cells (hCPCs) and promoted their cellular functions. Furthermore, rapamycin not only inhibited mTOR signaling but also influenced signaling pathways, including STAT3 and PIM1, in hCPCs. Therefore, these data reveal a crucial function for rapamycin in senescent hCPCs and provide clinical strategies based on chronic mTOR activity.
Highlights
Aging is associated with an organism progressively losing the ability to maintain homeostasis and repair tissue damage[1]
Senescent and dysfunctional resident human cardiac progenitor cells accumulate as a consequence of cardiac pathology[8,9,10,11,12] and lead to premature cardiac aging and heart failure[13]. These hCPCs act as key regulators of cardiomyocyte homeostasis in the heart[14,15] and contribute to the repair of damaged heart tissue[16]
HCPCs act as key regulators of cardiomyocyte homeostasis in the heart[14,15] and contribute to the repair of damaged heart tissue during aging[16]
Summary
Aging is associated with an organism progressively losing the ability to maintain homeostasis and repair tissue damage[1]. The predominant aging mechanism occurs because of the accumulation of senescent cells in various tissues and organs[2]. Senescent and dysfunctional resident human cardiac progenitor cells (hCPCs) accumulate as a consequence of cardiac pathology[8,9,10,11,12] and lead to premature cardiac aging and heart failure[13]. These hCPCs act as key regulators of cardiomyocyte homeostasis in the heart[14,15] and contribute to the repair of damaged heart tissue[16]
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