mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance.
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.
['Haller|Samantha|S|', 'Kapuria|Subir|S|', 'Riley|Rebeccah R|RR|', "O'Leary|Monique N|MN|", 'Schreiber|Katherine H|KH|', 'Andersen|Julie K|JK|', 'Melov|Simon|S|', 'Que|Jianwen|J|', 'Rando|Thomas A|TA|', 'Rock|Jason|J|', 'Kennedy|Brian K|BK|', 'Rodgers|Joseph T|JT|', 'Jasper|Heinrich|H|']
D053687:Adult Stem Cells D000818:Animals D004330:Drosophila D000076222:Mechanistic Target of Rapamycin Complex 1 D051379:Mice D018345:Mice, Knockout D012038:Regeneration D015398:Signal Transduction D020123:Sirolimus
regeneration somatic stem cell aging rapamycin intestine trachea muscle Drosophila mTOR metabolism