摘要
Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.
基金
supported by the National Natural Science Foundations of China 82230030 and 81871492(Y.L.),82201020(Y.W),and 82100980(S.S.J)
the Beijing Natural Science Foundation JL23002(Y.L.)and 7214305(S.S.J)
the Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)
the Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)
Ten-Thousand Talents Program QNBJ2019-2(Y.L.)
the Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)
Beijing Nova Program Z211100002121043(Y.W.)
China National Postdoctoral Program for Innovative Talents BX2021022(Y.W.),BX20200020(S.S.J)
China Postdoctoral Science Foundation 2021M700281(Y.W.)。
