Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In...Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In regenerative medicine,harnessing developmental principles for tissue repair offers promising therapeutic potential.Of particular interest is the condensation of progenitor cells,an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration.However,the precise cellular coordination mechanisms during condensation and regeneration remain elusive.Here,taking the tooth as a model organ,we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla,revealing a distinct Platelet-derived growth factor receptor alpha(PDGFRA)mesenchymal stem/stromal cell(MSC)population with remarkable odontogenic potential.Interestingly,a reciprocal paracrine interaction between PDGFRA^(+)dental follicle stem cells(DFSCs)and CD31^(+)Endomucin^(+)endothelial cells(ECs)was mediated by Vascular endothelial growth factor A(VEGFA)and Platelet-derived growth factor subunit BB(PDGFBB).This crosstalk not only maintains the functionality of PDGFRA^(+)DFSCs but also drives specialized angiogenesis.In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair.Collectively,our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis.These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.展开更多
Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandin...Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive.Here,we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell(MSC)function and regeneration.Interestingly,replenishment of cell aggregates-derived extracellular vesicles(CA-EVs)rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5.Importantly,in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice,suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration.Collectively,our findings provide insights into Golgi regulation in stem cell senescence and bone aging,which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.展开更多
Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely elucidated.Here,we reveal an o...Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely elucidated.Here,we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-adrenergic receptor(β2AR)signaling,critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4(Pdcd4),and mediated detrimental effects of both isoproterenol(ISO)and chronic variable stress(CVS)on bone.Intriguingly,without affecting osteoblastic bone formation,bone protection against ISO and CVS was sufficiently achieved by a(D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic mi R-21 or by clinically relevant drugs to suppress osteoclastogenesis.Collectively,these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.展开更多
Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines rema...Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines remains elusive.Here,we reveal that even under physiological conditions,MSCs produce and release a low level of tumor necrosis factor alpha(TNFα),which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling.Furthermore,TNFαcritically maintains MSC function in vivo during bone homeostasis.Mechanistically,we unexpectedly discovered that physiological levels of TNFαsafeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFαbinds to mammalian target of rapamycin(mTOR)complex 2 and restricts mTOR signaling.Importantly,inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFαdeficiency and mechanical unloading.Collectively,these findings unravel the physiological framework of the dynamic TNFαshuttlebased mTOR equilibrium that governs MSC and bone homeostasis.展开更多
Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach i...Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.展开更多
Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promo...Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promote immune tolerance,and a large number of apoptotic vesicles(apoVs)are generated from MSCs during apoptosis.In an effort to characterize these apoVs and explore their immunomodulatory potential,here we show that after replenishing them systemically,the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued,leading to the amelioration of inflammation and lupus activity.ApoVs directly interacted with CD4^(+)T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner.A broad range of Th1/2/17 subsets and cytokines including IFNγ,IL17A and IL-10 were suppressed while Foxp3^(+)cells were maintained.Mechanistically,exposed phosphatidylserine(PtdSer/PS)on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction.Remarkably,administration of apoVs prevented Th17 differentiation and memory formation,and ameliorated inflammation and joint erosion in murine arthritis.Collectively,our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4^(+)T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.展开更多
Stem cells remain in a quiescent state for long-term maintenance and preservation of potency;this process requires fine-tuning regulatory mechanisms.In this study,we identified the epigenetic landscape along the devel...Stem cells remain in a quiescent state for long-term maintenance and preservation of potency;this process requires fine-tuning regulatory mechanisms.In this study,we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells(SSCs)in skeletogenesis governed by a key regulator,Ptip(also known as Paxip1,Pax interaction with transcription-activation domain protein-1).Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs,and loss of Ptip in type II collagen(Col2)^(+)progenitors causes abnormal activation and differentiation of SSCs,impaired growth plate morphogenesis,and long bone dysplasia.We also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1(Pgk1)by repressing histone H3 lysine 27 acetylation(H3K27ac)at the promoter region.Notably,inhibition of glycolysis improved the function of SSCs despite Ptip deficiency.To the best of our knowledge,this is the first study to establish an epigenetic framework based on Ptip,which safeguards skeletal stem cell quiescence and potency through metabolic control.This framework is expected to improve SSC-based treatments of bone developmental disorders.展开更多
基金supported by grants from the National Key Research and Development Program of China(2022YFA1104400)the National Natural Science Foundation of China(82170988,82371020,82301028,82401201,82471011)+5 种基金the Young Science and Technology Rising Star Project of Shaanxi Province(2024ZC-KJXX-122)the China Postdoctoral Science Foundation(BX20230485)the Project of State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration(2024MS04)the Shaanxi Provincial Health Research and Innovation Platform Construction Plan(2024PT-04)the“Rapid Response”Research projects(2023KXKT017 and 2023KXKT090)the Intramural Research Program project founded by Fourth Military Medical University(2024QMJJ008).
文摘Periodontal bone defects,primarily caused by periodontitis,are highly prevalent in clinical settings and manifest as bone fenestration,dehiscence,or attachment loss,presenting a significant challenge to oral health.In regenerative medicine,harnessing developmental principles for tissue repair offers promising therapeutic potential.Of particular interest is the condensation of progenitor cells,an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration.However,the precise cellular coordination mechanisms during condensation and regeneration remain elusive.Here,taking the tooth as a model organ,we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla,revealing a distinct Platelet-derived growth factor receptor alpha(PDGFRA)mesenchymal stem/stromal cell(MSC)population with remarkable odontogenic potential.Interestingly,a reciprocal paracrine interaction between PDGFRA^(+)dental follicle stem cells(DFSCs)and CD31^(+)Endomucin^(+)endothelial cells(ECs)was mediated by Vascular endothelial growth factor A(VEGFA)and Platelet-derived growth factor subunit BB(PDGFBB).This crosstalk not only maintains the functionality of PDGFRA^(+)DFSCs but also drives specialized angiogenesis.In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair.Collectively,our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis.These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
基金supported by grants from the National Natural Science Foundation of China(81930025,82201013,82371020,82370949,82100992)the Young Science and Technology Rising Star Project of Shaanxi Province(2023KJXX-027)the China Postdoctoral Science Foundation(BX20230485).
文摘Healthy aging is a common goal for humanity and society,and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration.However,the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive.Here,we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell(MSC)function and regeneration.Interestingly,replenishment of cell aggregates-derived extracellular vesicles(CA-EVs)rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5.Importantly,in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice,suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration.Collectively,our findings provide insights into Golgi regulation in stem cell senescence and bone aging,which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.
基金supported by grants from the National Natural Science Foundation of China(81870796,82170988,81930025 and 82100969)the General Research Funds from the Research Grants Council of Hong Kong SAR(12114416,12100918,12136616 and 12103519)the China Postdoctoral Science Foundation(2019M663986 and BX20190380)。
文摘Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely elucidated.Here,we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-adrenergic receptor(β2AR)signaling,critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4(Pdcd4),and mediated detrimental effects of both isoproterenol(ISO)and chronic variable stress(CVS)on bone.Intriguingly,without affecting osteoblastic bone formation,bone protection against ISO and CVS was sufficiently achieved by a(D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic mi R-21 or by clinically relevant drugs to suppress osteoclastogenesis.Collectively,these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
基金This work was supported by grants from the National Institute of Dental and Craniofacial Research,National Institutes of Health,Department of Health and Human Services(K99E025915 to C.C.)a Schoenleber Pilot Research Grant(to S.S.)from the University of Pennsylvania School of Dental Medicine,the Guangdong Financial Fund for High-Caliber Hospital Construction,the Postdoctoral Innovative Talents Support Program of China(BX20190380 to B.S.)the General Program of the China Postdoctoral Science Foundation(2019M663986 to B.S.).
文摘Mesenchymal stem cells(MSCs)closely interact with the immune system,and they are known to secrete inflammatory cytokines in response to stress stimuli.The biological function of MSC-derived inflammatory cytokines remains elusive.Here,we reveal that even under physiological conditions,MSCs produce and release a low level of tumor necrosis factor alpha(TNFα),which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling.Furthermore,TNFαcritically maintains MSC function in vivo during bone homeostasis.Mechanistically,we unexpectedly discovered that physiological levels of TNFαsafeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFαbinds to mammalian target of rapamycin(mTOR)complex 2 and restricts mTOR signaling.Importantly,inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFαdeficiency and mechanical unloading.Collectively,these findings unravel the physiological framework of the dynamic TNFαshuttlebased mTOR equilibrium that governs MSC and bone homeostasis.
基金supported by grants from the National Key R&D Program of China(2021YFA1100600 to S.S.)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.,D-11 to X.K.)+5 种基金the Pearl River Talent Recruitment Program(2019ZT08Y485)the National Science and Technology Major Project of the Ministry of Science and Technology of China(2018ZX10302207-001-002)the Sun Yat-sen University Young Teacher Key Cultivation Project(18ykzd05 to X.K.)the Natural Science Foundation of Guangdong(2016A030313262 to X.M.)the National Natural Science Foundation of China(82170924 to X.K.,81700928 to L.M.)the Youth Teacher Training Project of Sun Yat-sen University(17ykpy71 to L.M.).
文摘Over 300 billion of cells die every day in the human body,producing a large number of endogenous apoptotic extracellular vesicles(apoEVs).Also,allogenic stem cell transplantation,a commonly used therapeutic approach in current clinical practice,generates exogenous apoEVs.It is well known that phagocytic cells engulf and digest apoEVs to maintain the body’s homeostasis.In this study,we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles.Mechanistically,apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern.The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension,which is associated with the mechanical force-regulated expression of DKK1 in circulation.Furthermore,we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells.This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.
基金This work was supported by grants from the State Scholarship Fund of China(201506240225to R.W.)the Pearl River Talent Recruitment Program(2019ZT08Y485,2019QN01Y138,2019JC01Y182)+2 种基金the National Key R&D Program of China(2021YFA1100600to S.S.)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.,C-03 and D-11 to X.K.)the National Natural Science Foundation of China(82170924to X.K.).
文摘Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promote immune tolerance,and a large number of apoptotic vesicles(apoVs)are generated from MSCs during apoptosis.In an effort to characterize these apoVs and explore their immunomodulatory potential,here we show that after replenishing them systemically,the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued,leading to the amelioration of inflammation and lupus activity.ApoVs directly interacted with CD4^(+)T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner.A broad range of Th1/2/17 subsets and cytokines including IFNγ,IL17A and IL-10 were suppressed while Foxp3^(+)cells were maintained.Mechanistically,exposed phosphatidylserine(PtdSer/PS)on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction.Remarkably,administration of apoVs prevented Th17 differentiation and memory formation,and ameliorated inflammation and joint erosion in murine arthritis.Collectively,our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4^(+)T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.
基金supported by the National Key Research and Development Program of China(2022YFA0103200)the National Natural Science Foundation of China(82325003,82230007,82200188,82270956 and 82171568)+1 种基金the National Defense Biotechnology Outstanding Young Talents Fund(01-SWKJYCJJ24)Shaanxi Province Innovation Capability Support Program Scientific and Technological Innovation Team(2023-CX-TD-69).
文摘Stem cells remain in a quiescent state for long-term maintenance and preservation of potency;this process requires fine-tuning regulatory mechanisms.In this study,we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells(SSCs)in skeletogenesis governed by a key regulator,Ptip(also known as Paxip1,Pax interaction with transcription-activation domain protein-1).Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs,and loss of Ptip in type II collagen(Col2)^(+)progenitors causes abnormal activation and differentiation of SSCs,impaired growth plate morphogenesis,and long bone dysplasia.We also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1(Pgk1)by repressing histone H3 lysine 27 acetylation(H3K27ac)at the promoter region.Notably,inhibition of glycolysis improved the function of SSCs despite Ptip deficiency.To the best of our knowledge,this is the first study to establish an epigenetic framework based on Ptip,which safeguards skeletal stem cell quiescence and potency through metabolic control.This framework is expected to improve SSC-based treatments of bone developmental disorders.
