Genetically enhanced mesenchymal stem cell therapy for aging and aging-related diseases

Yusheng Cai, PhD, Zeming Wu, PhD, Institute of Zoology, Chinese Academy of Sciences; Jinghui Lei, PhD, Wei Li, PhD, Lingling Geng, PhD, Si Wang, PhD, Xuanwu Hospital, Capital Medical University

Aging is the predominant risk for organ degeneration and then the onset of many chronic diseases, including liver cirrhosis, chronic obstructive pulmonary disease, and cardiovascular diseases. Harnessing single-cell sequencing techniques, we captured the aging landscapes of aorta and coronary arteries in non-human primate, and further characterized FOXO3A, a longevity-associated transcription factor, as a master regulator gene that was downregulated in six subtypes of monkey vascular cells during aging. Based on the important clue, we developed genetically enhanced human mesenchymal stem cells (MSCs), a well-known stem cell source for regenerative therapy, by recoding two nucleotides in FOXO3 gene to activate its activity constitutively. MSCs contribute directly to the homeostatic maintenance of the organs they reside, and their dysfunction is considered one of the driving forces for deleterious changes in organs during aging. MSC therapy has been established as a promising approach to treat multiple inflammatory disorders or ischemic conditions due to their immune-modulatory and angiogenic properties. However, the efficacy and safety of MSC therapy for aging and its related diseases haven’t been well studied yet. Our genetically enhance strategy reinforced the MSC more robust regenerative capacities and a reduced risk for tumorigenesis. Additionally, these cells exhibited increased resistance to multiple stresses and cellular senescence, elevated regenerative capacity and reduced transformation potential. Moreover, FOXO3- genetically-enhanced human MSCs could effectively promote cardiac repair after mouse myocardial infarction. Collectively, our study demonstrated the superiority and safety of this MSC enhancement strategy and opened a new avenue for the stem cell treatment of aging-related diseases.