mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

Publication date: 7 December 2017
Source:Cell Stem Cell, Volume 21, Issue 6
Author(s): Samantha Haller, Subir Kapuria, Rebeccah R. Riley, Monique N. O'Leary, Katherine H. Schreiber, Julie K. Andersen, Simon Melov, Jianwen Que, Thomas A. Rando, Jason Rock, Brian K. Kennedy, Joseph T. Rodgers, Heinrich Jasper
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.

Graphical abstract

Teaser

Studying flies and mice, Jasper and colleagues demonstrate that repeated regenerative episodes result in the loss of tissue stem cells (SCs) due to the transient activation of the growth regulator mTORC1 during SC activation. Pharmacological inhibition of mTORC1 can prevent this loss and limit the age-related decline in SC numbers.


http://ift.tt/2BWr23q