mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIDCR	STEMCELL-1

Authors

• R Iglesias-Bartolome
• V Patel
• A Cotrim
• K Leelahavanichkul
• AA Molinolo
• JB Mitchell
• JS Gutkind

Abstract

The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. The mammalian target of rapamycin (mTOR) plays a central role in the regulation of cell growth and cancer progression, but paradoxically increased mTOR activity can also cause cells to undergo differentiation or senescence, thereby exiting the proliferative adult stem cell pool. We explored and exploited this differential effect of rapamycin in normal and transformed oral epithelial cells in order to protect normal oral epithelia against the deleterious effects of radiation. We show that mTOR inhibition protects from the senescence and consequent depletion of human adult oral epithelial progenitor cells during both replicative senescence and upon ionizing radiation. In vivo, inhibition of mTOR protects from the loss of proliferative epithelial progenitor stem cells upon radiation and enhances their tissue repopulating capacity, therefore preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.

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