Rejuvenation of airway basal stem cells by partial chemical reprogramming Mengyu Zou1, Qiaoyu Chen1, Ying Hua1, Wei Zuo1,2* 1Tongji Stem Cell Center, Tongji University, Shanghai, China 2Kiangnan Institute of Stem Cell, Hangzhou, China

Function of adult stem cells decline with age. Very limited intervention has been developed to slow down or reverse the biological aging of human adult stem cells. In current study, we report partial reprogramming of the human basal airway stem cells into a biologically younger status. We studied airway basal cells cloned from 44 human donors, and found that stem cells from old donors (>60 yrs) demonstrated aging-related phenotypes such as elongated cell shape, cellular senescence, attenuated regenerative capacity and increased pro-inflammation properties. Such aging phenotype could be efficiently eliminated by partial reprogramming with 9 chemical compounds in culture. Transcriptomic clock analysis showed that partial reprogramming achieved averagely 18.6 years reversal of biological ages in stem cells, which was confirmed by epigenetic clock analysis. Upon transplantation into injured mouse lung, the rejuvenated human airway stem cells demonstrated improved repairing function and significantly increased survival rate of mice as compared to the untreated aged cells. Altogether, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged human stem cells and warrant further application of the approaches for cell therapy.