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TSG Enhances Hematopoietic Stem Cell Lymphoid Differentiationand Function via AMPK in Mice

Yongfang Ding;Li Cui;Yingjie Wei;Luan Shu;Yunru Peng

  With age, haematopoietic stem cells(HSCs) weaken their ability to regenerate the blood system, especially lymphopoiesis, and promote disease development. Adenosine monophosphate(AMP) activated protein kinase(AMPK) as a central regulator of energy homeostasis, whose activation exhibit a multitude of health benefits including HSCs aging and myeloid-biased differentiation, has been attracted considerable attention to develop AMPK activators. However, scarcely any activator regarding HSCs lymphoid differentiation and function is documented. Here a ‘senolyticpharmacological agent stilbene glycoside(TSG) improves regenerative capacity and lymphoid differentiation in HSCs aging mainly through AMPK activation. Oral administration of TSG to either normally aged mice or sublethally irradiated effectively increased the absolute number of common lymphoid progenitor(CLP) cells as well as its downstream B and T lymphocytes in different developmental stages, whereas without any changes in the number of HSCs and myeloid cells. Moreover, TSG also significantly increased donor chimerism to enhance the HSCs/CLPs repopulation potential of old mice through HSCs and CLPs transplantation, even revert to the level of young donors. Finally, TSG is revealed to activate AMPK by both directly binding with the α subunit and reducing ATP level for maintaining HSCs quiescence to rejuvenate the HSCs aging. Our results demonstrate that TSG might be a promising anti-aging agent to restore immuno-competence and hematopoietic reconstitution by activating AMPK in aging individuals characterized as deterioration in differentiation toward the lymphoid lineage and regenerative capacity.……