Chinese scientists have discovered a small molecule metabolite that promotes multi-tissue regeneration and delays aging

2022-05-09 0 By

Regeneration is an important process for the body to repair damaged, diseased or aging tissues.From lower animals to humans, different species have different degrees of regenerative ability, and this ability gradually decreases with the evolution of species.For example, salamanders in lower animals can fully regenerate a severed limb, while most mammals, including humans, have only limited regenerative and damage repair abilities.Antlers are the only organ in mammals that can fully regenerate.Although highly evolved species can initiate regenerative repair programs when tissue is damaged, the ability of regenerative repair decreases with age.Stem cells are known to play a key role in the process of tissue regeneration and repair.Salamanders, for example, can regenerate limbs by forming blastema tissue, a group of dry cells that are dedifferentiated.Similarly, during the annual antler regeneration process, antler antler stem cells located in the periosteum of the antler can differentiate to produce complete antler organs including blood vessels, cartilage, bone, dermis and nerves.Human adult stem cells, such as mesenchymal stem cells, play a key role in the regeneration and repair of many tissues and organs, but their number and regenerative capacity also decline with age.Although it has been found that the regenerative ability of the body is gradually lost with evolution and aging, the molecular mechanism is not clear.Endogenous small molecule metabolites were relatively conserved among different species.However, little is known about the small molecule metabolites that regulate aging and regeneration until now.Through to the regeneration process of the lower animals nature study, and to have strong regeneration ability of young group and stem cell study, conservative theory is expected to be found across species, key metabolic regulation of renewable and aging of small molecules, thereby to decode regeneration metabolic regulation and control mechanism, found the key to promote regeneration and anti-aging metabolites provide new clues and ideas.Liu Guanghui and Qu Jing, Institute of Zoology, Chinese Academy of Sciences, And Weiqi Zhang, Institute of Genomics, Chinese Academy of Sciences, Beijing, ChinaCross-species Metabolomic Analysis of identifies uridine as a potent regeneration factor.In this study, the cross-species, cross-age and cross-tissue metabolic molecular characteristics were analyzed in depth, the metabolic regulatory pathways closely related to higher regenerative capacity were decoded, and a series of key pathways and small molecule metabolites were identified that could be modified to delay aging and promote multi-tissue regeneration of human stem cells.It provides potential molecular markers and intervention strategies for scientific evaluation of aging, prevention and treatment of aging-related diseases, and development of regenerative medicine.The study mapped metabolism across multiple cell types across species, ages, and tissues, including:The blastema of ambrosalamander limb regeneration, deer antlet stem cells, a variety of tissues (brain, heart, liver, muscle, kidney, fat, skin, blood) of young and old cynostomy monkeys, and mesenchymal stem cells of young and old cynostomy monkeys systematically reveal some conserved and regeneration-related metabolic pathways across species.For example, biosamples with high regenerative capacity tended to be enriched in polyamine metabolism, uracil metabolism, and fatty acid metabolic pathways.Further combining with the aging research platform of human stem cells, we carefully screened the potential metabolites promoting regeneration, and found that the small molecule metabolite Uridine can significantly improve the self-renewal ability of aging human mesenchymal stem cells.Further studies showed that uridine treatment assisted the regeneration and repair of damaged or diseased tissues in 5 mouse tissue injury models (muscle injury model, liver fibrosis model, hair regeneration model, myocardial infarction model and arthritis model).In the muscle injury model, uridine effectively enhanced the regeneration and repair ability of muscle, alleviated the inflammatory response caused by muscle injury, and enhanced the grasping strength and systematic movement ability of the mice.In the liver fibrosis model, uridine alleviated the liver fibrosis induced by carbon tetrachloride and effectively improved several physiological indexes of liver function.In the hair regeneration model, uridine treatment can stimulate the hair follicle to enter the growth phase in advance, thus promoting the hair growth.In myocardial infarction model, uridine can effectively relieve acute inflammation and improve the contractility of injured heart.In the arthritis model, uridine can promote the regeneration of articular cartilage and improve the joint motor ability of mice.These results suggest that uridine, a single metabolite, can promote the regeneration and repair process of mammalian multi-organ tissues.Consistent with the higher regenerative capacity of younger individuals, younger individuals have higher levels of uridine in their blood than older individuals.Next, the researchers investigated whether uridine treatment could enhance physiological function in older individuals.The results showed that two months of oral uridine treatment enhanced physiological function in elderly mice (22 months of age), showing significant improvement in limb grasping and motor ability.These findings support the potential activity of uridine in inhibiting senescence of human stem cells, promoting multitissue regeneration and repair, and improving physiological function of elderly individuals from multiple levels.This study provides the first comprehensive map of endogenous metabolites across species, ages, and tissues, and systematically elucidates the molecular metabolic pathways associated with strong regenerative capacity.More importantly, the study found that uridine is a key metabolite that can delay the senescence of human stem cells and promote multi-tissue regeneration and repair in mammals.These findings lay a theoretical foundation for further understanding the mechanism of body injury or pathological repair, and provide new strategies for improving the health of the elderly population, preventing and treating age-related diseases.The study of the relevant data has been uploaded to the old at the same time omics database Aging Atlas (https://bigd.big.ac.cn/aging/index) and Regeneration of omics database RegenerationRoadmap (https://ngdc.cncb.ac.cn/aging/index).The research was carried out in collaboration with the Institute of Zoology, Chinese Academy of Sciences, Beijing Institute of Stem Cell and Regenerative Medicine, Xuanwu Hospital, Capital Medical University, Beijing Institute of Genomics, Chinese Academy of Sciences (National Center for Bioinformatics), Beijing Hospital, Peking University Third Hospital and other institutions.Guanghui Liu and Jing Qu, Institute of Zoology, Chinese Academy of Sciences, and Weiqi Zhang, Beijing Institute of Genomics, Chinese Academy of Sciences, are co-corresponding authors of this paper.Zunpeng Liu, PhD candidate from Institute of Zoology, Chinese Academy of Sciences, Wei Li and Lingling Geng, Assistant researcher from Xuanwu Hospital, Capital Medical University, Liang Sun, Beijing Hospital, Qiaoran Wang, PhD candidate from Beijing Institute of Genomics, Chinese Academy of Sciences, and Yang Yu, Third Hospital, Peking University, are co-first authors of the paper.This study was supervised and supported by Prof. Han Jingdong from Peking University, Prof. Ren Jie from Beijing Institute of Genomics, Chinese Academy of Sciences, Prof. Song Moshi and Prof. Huang Shiqiang from Institute of Zoology, Chinese Academy of Sciences, Prof. Wang Si from Xuanwu Hospital of Capital Medical University, and Prof. Li Chunyi from Changchun Institute of Science and Technology.At the same time, the project has been supported by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and Beijing Municipal Government.The thesis links: https://www.nature.com/articles/s41421-021-00361-3