Unlike adult mammalian heart,zebrafish heart has a remarkable capacity to regenerate after injury.Previous study has shown Notch signaling activation in the endocardium is essential for regeneration of the myocardium ...Unlike adult mammalian heart,zebrafish heart has a remarkable capacity to regenerate after injury.Previous study has shown Notch signaling activation in the endocardium is essential for regeneration of the myocardium and this activation is mediated by hemodynamic alteration after injury,however,the molecular mechanism has not been fully explored.In this study we demonstrated that blood flow change could be perceived and transmitted in a primary cilia dependent manner to control the hemodynamic responsive klf2 gene expression and subsequent activation of Notch signaling in the endocardium.First we showed that both homologues of human gene KLF2 in zebrafish,klf2a and klf2b,could respond to hemodynamic alteration and both were required for Notch signaling activation and heart regeneration.Further experiments indicated that the upregulation of klf2 gene expression was mediated by endocardial primary cilia.Overall,our findings reveal a novel aspect of mechanical shear stress signal in activating Notch pathway and regulating cardiac regeneration.展开更多
The primary cilium,as a mechanical receptor of osteocytes,participates in the regulation of osteocyte mechanosensitivity.However,how the length of osteocyte primary cilia changes with fluid shear stress(FSS)are unclea...The primary cilium,as a mechanical receptor of osteocytes,participates in the regulation of osteocyte mechanosensitivity.However,how the length of osteocyte primary cilia changes with fluid shear stress(FSS)are unclear,and how the mechanical transmission within osteocytes altered by primary cilia is not well understood yet.Therefore,the ciliary length changes of osteocyte under 15dyn/cm2 of FSS were experimentally detected,and then 3D finite element models of osteocyte primary cilia containing the basal body and axoneme were built.The results showed that(1)The ciliary length of the CON group,FSS 1h,and FSS 6h were 3.71±1.34μm,3.79±1.04μm,and 1.24±0.73μm respectively,indicating the different durations of FSS might lead to the adaptive changes of cilium length.The calculations showed(2)when the ciliary length became shorter with the ciliary angle stayed the same,the deformation and stress of the cell membrane and membrane skeleton was increased.However,the deformation and stress of the cilia membrane,basal body,the rotation angles of basal body were decreased,and those of cytoplasm,cytoskeleton,actin cortex and nucleus were also decreased;(3)With the decrease of the ciliary angle,the deformation and stress of the cilia membrane,basal body,as well as the rotation angles of basal body were increased.Those of the cytoplasm,cytoskeleton,actin cortex,and nucleus were also increased except the cell membrane and membrane skeleton.The calculation results suggested the length and angle of the primary cilia,the deformation and stress of intracellular structures in osteocyte were altered with ciliary basal body,indicated the connection between the basal body and cytoskeleton may be a key factor that affected the mechanical transport in osteocytes across the cell membrane.This finally promoted the adaptive change of ciliary length under FSS.展开更多
Osteocytes,the primary cells in bone,play a crucial role in sensing external load environments and regulating other bone cells.Due to the piezoelectric effect of the mineralized matrix and collagen that make up bone,t...Osteocytes,the primary cells in bone,play a crucial role in sensing external load environments and regulating other bone cells.Due to the piezoelectric effect of the mineralized matrix and collagen that make up bone,the mechanical stimulus received is converted into an electrical stimulus to affect the reconstruction of bone.Despite the importance of osteocyte,many studies have focused on the mechanical loading and fluid flow of it,there is still a gap in the study of the piezoelectric effects of various mechanosensors on the microscale.In this paper,we developed a finite element model of osteocytes that incorporates the piezoelectric bone matrix.This model is comprehensive,comprising the osteocyte cell body enclosed by lacuna,osteocyte processes enclosed by canaliculi,and the interposed charged ionic fluid.Additionally,it features mechanosensors such as collagen hillocks and primary cilia.In our study,we subjected the piezoelectric bone matrix model to triaxial displacement,subsequently assessing the electrical signal variations across different mechanosensors within the osteocyte.The observed disparities in mechanical perception by various mechanosensors were primarily attributable to greater liquid velocity changes in the polarization direction as opposed to other directions.Collagen hillocks showed insensitivity to piezoelectric signals,serving predominantly to mechanically transmit signals through solid-to-solid contact.In contrast,processes and primary cilia were highly responsive to piezoelectric signals.Interestingly,the processes oriented in the direction of the electric field demonstrated a differential piezoelectric signal perception compared to those in other directions.Primary cilia were especially sensitive to fluid flow pressure changes,which were influenced both by loading rates and external piezoelectric effects.Overall,our findings illuminate the complexity of mechanical perception within osteocytes in a piezoelectric environment.This adds a new dimension to our understanding and suggests avenue展开更多
Bone and teeth are hard tissues.Hard tissue diseases have a serious effect on human survival and quality of life.Primary cilia are protrusions on the surfaces of cells.As antennas,they are distributed on the membrane ...Bone and teeth are hard tissues.Hard tissue diseases have a serious effect on human survival and quality of life.Primary cilia are protrusions on the surfaces of cells.As antennas,they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis.Mutations in cilium-related genes result in a variety of developmental and even lethal diseases.Patients with multiple ciliary gene mutations present overt changes in the skeletal system,suggesting that primary cilia are involved in hard tissue development and reconstruction.Furthermore,primary cilia act as sensors of external stimuli and regulate bone homeostasis.Specifically,substances are trafficked through primary cilia by intraflagellar transport,which affects key signaling pathways during hard tissue development.In this review,we summarize the roles of primary cilia in long bone development and remodeling from two perspectives:primary cilia signaling and sensory mechanisms.In addition,the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described.We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.展开更多
基金We thank Haitao Zhou and Lifeng Li for fish care,Kaa Seng Lai,Yabo Fang and Wenyan Li for technical support and other lab members for in depth discussion.We thank Dr Tao Zhong for providing reagents.This study was supported by National Key R&D Program of China grant 2018YFA0801004 and NSFC grant 31571492 to R.Z.
文摘Unlike adult mammalian heart,zebrafish heart has a remarkable capacity to regenerate after injury.Previous study has shown Notch signaling activation in the endocardium is essential for regeneration of the myocardium and this activation is mediated by hemodynamic alteration after injury,however,the molecular mechanism has not been fully explored.In this study we demonstrated that blood flow change could be perceived and transmitted in a primary cilia dependent manner to control the hemodynamic responsive klf2 gene expression and subsequent activation of Notch signaling in the endocardium.First we showed that both homologues of human gene KLF2 in zebrafish,klf2a and klf2b,could respond to hemodynamic alteration and both were required for Notch signaling activation and heart regeneration.Further experiments indicated that the upregulation of klf2 gene expression was mediated by endocardial primary cilia.Overall,our findings reveal a novel aspect of mechanical shear stress signal in activating Notch pathway and regulating cardiac regeneration.
基金National Natural Science Foundation of China(11972068,12002026).
文摘The primary cilium,as a mechanical receptor of osteocytes,participates in the regulation of osteocyte mechanosensitivity.However,how the length of osteocyte primary cilia changes with fluid shear stress(FSS)are unclear,and how the mechanical transmission within osteocytes altered by primary cilia is not well understood yet.Therefore,the ciliary length changes of osteocyte under 15dyn/cm2 of FSS were experimentally detected,and then 3D finite element models of osteocyte primary cilia containing the basal body and axoneme were built.The results showed that(1)The ciliary length of the CON group,FSS 1h,and FSS 6h were 3.71±1.34μm,3.79±1.04μm,and 1.24±0.73μm respectively,indicating the different durations of FSS might lead to the adaptive changes of cilium length.The calculations showed(2)when the ciliary length became shorter with the ciliary angle stayed the same,the deformation and stress of the cell membrane and membrane skeleton was increased.However,the deformation and stress of the cilia membrane,basal body,the rotation angles of basal body were decreased,and those of cytoplasm,cytoskeleton,actin cortex and nucleus were also decreased;(3)With the decrease of the ciliary angle,the deformation and stress of the cilia membrane,basal body,as well as the rotation angles of basal body were increased.Those of the cytoplasm,cytoskeleton,actin cortex,and nucleus were also increased except the cell membrane and membrane skeleton.The calculation results suggested the length and angle of the primary cilia,the deformation and stress of intracellular structures in osteocyte were altered with ciliary basal body,indicated the connection between the basal body and cytoskeleton may be a key factor that affected the mechanical transport in osteocytes across the cell membrane.This finally promoted the adaptive change of ciliary length under FSS.
基金supported by the National Natural Science Foundation of China(Grant Nos.12272250,12372310,and 82172503)China Postdoctoral Science Foundation(Grant No.2020M680913)+1 种基金Shanxi Scholarship Council of China(Grant No.2022081)Shanxi Province Graduate Education Innovation Program(Grant Nos.2022Y278 and 2023-125).
文摘Osteocytes,the primary cells in bone,play a crucial role in sensing external load environments and regulating other bone cells.Due to the piezoelectric effect of the mineralized matrix and collagen that make up bone,the mechanical stimulus received is converted into an electrical stimulus to affect the reconstruction of bone.Despite the importance of osteocyte,many studies have focused on the mechanical loading and fluid flow of it,there is still a gap in the study of the piezoelectric effects of various mechanosensors on the microscale.In this paper,we developed a finite element model of osteocytes that incorporates the piezoelectric bone matrix.This model is comprehensive,comprising the osteocyte cell body enclosed by lacuna,osteocyte processes enclosed by canaliculi,and the interposed charged ionic fluid.Additionally,it features mechanosensors such as collagen hillocks and primary cilia.In our study,we subjected the piezoelectric bone matrix model to triaxial displacement,subsequently assessing the electrical signal variations across different mechanosensors within the osteocyte.The observed disparities in mechanical perception by various mechanosensors were primarily attributable to greater liquid velocity changes in the polarization direction as opposed to other directions.Collagen hillocks showed insensitivity to piezoelectric signals,serving predominantly to mechanically transmit signals through solid-to-solid contact.In contrast,processes and primary cilia were highly responsive to piezoelectric signals.Interestingly,the processes oriented in the direction of the electric field demonstrated a differential piezoelectric signal perception compared to those in other directions.Primary cilia were especially sensitive to fluid flow pressure changes,which were influenced both by loading rates and external piezoelectric effects.Overall,our findings illuminate the complexity of mechanical perception within osteocytes in a piezoelectric environment.This adds a new dimension to our understanding and suggests avenue
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.82061130222,81822012,81771043,92049201,81770873,and 81802193)the National Science and Technology Major Project of China(No.2016YFC1102705)+1 种基金the Shanghai Academic Leader of Science and Technology Innovation Action Plan(No.20XD1424000)the Shanghai Experimental Animal Research Project of Science and Technology Innovation Action Plan(No.8191101676).
文摘Bone and teeth are hard tissues.Hard tissue diseases have a serious effect on human survival and quality of life.Primary cilia are protrusions on the surfaces of cells.As antennas,they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis.Mutations in cilium-related genes result in a variety of developmental and even lethal diseases.Patients with multiple ciliary gene mutations present overt changes in the skeletal system,suggesting that primary cilia are involved in hard tissue development and reconstruction.Furthermore,primary cilia act as sensors of external stimuli and regulate bone homeostasis.Specifically,substances are trafficked through primary cilia by intraflagellar transport,which affects key signaling pathways during hard tissue development.In this review,we summarize the roles of primary cilia in long bone development and remodeling from two perspectives:primary cilia signaling and sensory mechanisms.In addition,the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described.We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.
