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

• Published in: Experimental & molecular medicine 2020, 52(0), , pp.1-14
• Main Authors: Park, Ji Hye, Lee, Na Kyoung, Lim, Hye Ji, Ji, Seung taek, Kim, Yeon-Ju, Jang, Woong Bi, Kim, Da Yeon, Kang, Songhwa, Yun, Jisoo, Ha, Jong seong, Kim, Hyungtae, Lee, Dongjun, Baek, Sang Hong, Kwon, Sang-Mo
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 14/63; 38; 38/1; 38/90; 38/91; 42/100; 42/34; 45/90; 631/532/2118; 631/532/2440; Aging; Biomedical and Life Sciences; Biomedicine; Cardiac muscle; Cell cycle; Cell differentiation; Congestive heart failure; Embryo cells; Heart diseases; Homeostasis; Medical Biochemistry; Molecular Medicine; Myocardial infarction; Progenitor cells; Rapamycin; Senescence; Signal transduction; Stat3 protein; Stem cell transplantation; Stem Cells; TOR protein; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-020-0374-4

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. Cardiac regeneration: preventing premature ageing Disrupting the mTOR signaling pathway, a major regulator of cell growth, protects human cardiac progenitor cells (hCPCs) from irreversible cell cycle arrest, also known as replicative cell senescence. Accumulation of senescent (aging) hCPCs leads to premature cardiac ageing and heart failure by hindering tissue repair in response to damage. Previous studies have shown that the mTOR inhibitor rapamycin promotes the differentiation of embryonic stem cells into hCPCs, but little is known about its effects on senescent hCPCs. Ji Hye Park at Pusan National University in South Korea and colleagues found that rapamycin reduced the expression of senescence-related markers in hCPCs and improved the ability of hCPCs to proliferate, migrate, and differentiate into cardiac muscle cells. These findings suggest that rapamycin could be used to aid cardiac regeneration following heart muscle damage caused by a heart attack.