mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema

Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTert CI ), is expressed from the p21 Cdkn1a locus. Expression of either TERT or TERT CI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERT CI . Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema. Synopsis Telomerase promotes tissue rejuvenation by counteracting cellular senescence and sustaining stem cells. This study presents mouse models that express either mTert or catalytically inactive mTert CI under the control of the p21 promoter to unravel the underlying mechanism. mTert but not mTert CI reduces age-dependent accumulation of senescent cells in lungs and restrains emphysema development. mTert promotes proliferation of a subclass of CD34+ endothelial progenitors and sustains capillary density in aged mice. p21-driven expression of mTert prevents emphysema in young mice exposed to VEGFR inhibitor under chronic hypoxia. mTert and mTert CI reduce accumulation of p21-positive cells in lungs with age, revealing a non-canonical activity of Tert. Telomerase promotes tissue rejuvenation by counteracting cellular senescence and sustaining stem cells. This study presents mouse models that express either mTert or catalytically inactive mTert CI under the control of the p21 promoter to unravel the underlying mechanism.