背景:骨的形成是一个动态的过程,破骨细胞和成骨细胞参与该动态过程。Semaphorin家族最早是作为轴突导向分子而被发现,其在许多不同组织里面表达并调节很多生理过程,近来更发现其在调节破骨细胞和成骨细胞方面发挥了重要作用。目的:总结...背景:骨的形成是一个动态的过程,破骨细胞和成骨细胞参与该动态过程。Semaphorin家族最早是作为轴突导向分子而被发现,其在许多不同组织里面表达并调节很多生理过程,近来更发现其在调节破骨细胞和成骨细胞方面发挥了重要作用。目的:总结Semaphorin家族各因子在骨动态平衡中发挥的作用。方法:应用计算机检索Pub Med和Web of science数据库中1993年6月至2014年1月关于Semaphorin家族各因子调控骨代谢的文章,以"semaphorin,sema"为检索词进行检索;排除与研究内容无关和内容重复的文章,保留48篇文章进行综述。结果与结论:semaphorins在骨的细胞生物学方面是一类新型的调控分子,研究显示semaphorins通过一些特殊的机制很活跃的参与了骨的重塑过程,semaphorin家族蛋白在骨自身动态平衡中很关键,这些发现给治疗骨质疏松、骨硬化症、关节假体旁骨溶解等骨病提供了一种新颖的方法及治疗靶点。展开更多
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune sema...Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune semaphorins＇, are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses： their functions in cell-cell interactions and their involvement in immune cell trafficking.展开更多
Plexins and semaphorins are a large family of proteins that are involved in cell movement and response.The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including t...Plexins and semaphorins are a large family of proteins that are involved in cell movement and response.The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous(Nkyimbeng-Takwi and Chapoval,2011;McCormick and Leipzig,2012;Yaron and Sprinzak,2012),epithelial(Miao et al.,1999;Fujii et al.,2002),and immune systems(Takamatsu and Kumanogoh,2012)as well as diverse cell processes including angiogenesis(Serini et al.,2009;Sakurai et al.,2012),embryogenesis(Perala et al.,2012),and cancer(Potiron et al.,2009;Micucci et al.,2010).Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin do-main(Hota and Buck,2012).The plexins and sema-phorins are divided into four and eight subfamilies respectively based on their structural homology.Semaphorins are relatively small proteins containing the extracellular semaphorin domain and short intra-cellular tails.Plexins contain the semaphorin domain and long intracellular tails(Hota and Buck,2012).The majority of plexin and semaphorin research has fo-cused on the nervous system,particularly the devel-oping nervous system,where these proteins are found to mediate many common neuronal cell processes including cell movement,cytoskeletal rearrangement,and signal transduction(Choi et al.,2008;Takamatsu et al.,2010).Their roles in the immune system are the focus of this review.展开更多
Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows...Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.展开更多
文摘背景:骨的形成是一个动态的过程,破骨细胞和成骨细胞参与该动态过程。Semaphorin家族最早是作为轴突导向分子而被发现,其在许多不同组织里面表达并调节很多生理过程,近来更发现其在调节破骨细胞和成骨细胞方面发挥了重要作用。目的:总结Semaphorin家族各因子在骨动态平衡中发挥的作用。方法:应用计算机检索Pub Med和Web of science数据库中1993年6月至2014年1月关于Semaphorin家族各因子调控骨代谢的文章,以"semaphorin,sema"为检索词进行检索;排除与研究内容无关和内容重复的文章,保留48篇文章进行综述。结果与结论:semaphorins在骨的细胞生物学方面是一类新型的调控分子,研究显示semaphorins通过一些特殊的机制很活跃的参与了骨的重塑过程,semaphorin家族蛋白在骨自身动态平衡中很关键,这些发现给治疗骨质疏松、骨硬化症、关节假体旁骨溶解等骨病提供了一种新颖的方法及治疗靶点。
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
文摘Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune semaphorins＇, are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses： their functions in cell-cell interactions and their involvement in immune cell trafficking.
文摘Plexins and semaphorins are a large family of proteins that are involved in cell movement and response.The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous(Nkyimbeng-Takwi and Chapoval,2011;McCormick and Leipzig,2012;Yaron and Sprinzak,2012),epithelial(Miao et al.,1999;Fujii et al.,2002),and immune systems(Takamatsu and Kumanogoh,2012)as well as diverse cell processes including angiogenesis(Serini et al.,2009;Sakurai et al.,2012),embryogenesis(Perala et al.,2012),and cancer(Potiron et al.,2009;Micucci et al.,2010).Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin do-main(Hota and Buck,2012).The plexins and sema-phorins are divided into four and eight subfamilies respectively based on their structural homology.Semaphorins are relatively small proteins containing the extracellular semaphorin domain and short intra-cellular tails.Plexins contain the semaphorin domain and long intracellular tails(Hota and Buck,2012).The majority of plexin and semaphorin research has fo-cused on the nervous system,particularly the devel-oping nervous system,where these proteins are found to mediate many common neuronal cell processes including cell movement,cytoskeletal rearrangement,and signal transduction(Choi et al.,2008;Takamatsu et al.,2010).Their roles in the immune system are the focus of this review.
基金supported by the National Natural Science Foundation of China,Nos.31971277(to DBY),31950410551(to DBY)Scientific Research Foundation for Returned Scholars,Ministry of Education of China(to DBY)+2 种基金a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(to DBY)the Postgraduate Research&Practice Innovation Program of Jiangsu Province of China,No.KYCX 19-2050(to JS)Jiangsu College Students’Innovation and Entrepreneurship Training Program,No.202213993005Y(to YY)。
文摘Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.
