Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells

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.

Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair

“…Treatment of MSCs with rapamycin for 24 h significantly alleviated cellular senescence, which was accompanied by reduced ROS production and the downregulation of p-Jun N-terminal kinases (JNK) and p-38 27 . Our previous study also demonstrated that chronic inhibition of mTOR by rapamycin attenuated cellular senescence and markedly improved the functions of hCSCs 14 . As shown in this study, we demonstrated that MHY-1685 also inhibited mTOR signaling in hCSCs, resulting in a higher cellular survival rate in the presence of oxidative stress, an increased proliferation rate with a short cell population doubling time, and the sustained stemness with differentiation potential.…”

“…Recent studies have reported that autophagy plays a role in the modulation of cell proliferation, differentiation, and senescence. Our previous study suggested that the autophagy inducer rapamycin reduced the senescence of hCSCs and improved cellular activities 14 . To establish whether MHY-1685 modulates autophagy signaling, we assessed the expression of an autophagy signal regulator protein (mTOR) by western blotting.…”

“…In addition, repeatedly expanded cells have a problem in that their telomeres gradually shorten with each round of DNA replication, and a critical length that inhibits further replication is eventually reached, causing the cell division to stop and the cell viability to become reduced 13 . This replicative senescence decreases the therapeutic potential of hCSCs not only by activating a senescence-associated secretory phenotype (SASP) but also by inhibiting proliferation and differentiation 14 . Therefore, the discovery of novel function-modulating factors by which hCSCs manage to escape senescence may ultimately help in terms of enhancing the effectiveness and improving the safety of therapeutic strategies.…”

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

“…Agreeing data were provided, indicating that these mTORC1 inhibitors operate via different mechanisms to inhibit the SASP, contributing to the up-regulation of DNA repair proteins and associated post-transcriptional modifications [ 174 , 176 ]. Importantly, inhibition of the mTOR pathway has already been reported to result not only in anti-senescence but also in anti-atherosclerotic effects [ 177 , 178 , 179 ].…”

“…Moreover, decreased arterial expression of the senescence marker p19, age-associated vascular dysfunction and oxidative stress reversal were observed upon dietary intake of rapamycin [ 277 ]. A recent study also revealed that mTORC1 inhibition mediated by rapamycin strongly weakened replicative senescence in human cardiac progenitor cells [ 177 ], which may open avenues to develop novel therapies. Moreover, statins were reported to inhibit the SASP and participate in the regulation of the cell cycle and telomerase, delaying both EC and T-cell senescence [ 278 ].…”