<正>Nerve repair after spinal cord injury(SCI)requires orderly growth,migration,and transmission of neuronal signals in the regenerated nerve fibers at the injury site.Neuronal apoptosis occurs at the site of in...<正>Nerve repair after spinal cord injury(SCI)requires orderly growth,migration,and transmission of neuronal signals in the regenerated nerve fibers at the injury site.Neuronal apoptosis occurs at the site of injury,so a regional'barrier'forms,and the nerve fibers cannot be reconstructed in an orderly manner.展开更多
Growth,development,aging,and disease occurrence in organisms,especially animals or Homo sapiens,are regulated by different regulatory systems in vivo.The nervous,endocrine,metabolic,and immune systems are the traditio...Growth,development,aging,and disease occurrence in organisms,especially animals or Homo sapiens,are regulated by different regulatory systems in vivo.The nervous,endocrine,metabolic,and immune systems are the traditional biological systems essential for the growth,development,and metabolism of the body.These systems maintain a balance and precisely biologically regulate every aspect of life activities under normal circumstances.However,in abnormal situations,owing to endogenous or exogenous attack,these regulatory systems result in dysfunction,subsequently leading to illness or injury(Muggianu et al.,2018).In the classical neuroendocrine regulatory system,Cushing’s syndrome is defined as a series of abnormal clinical symptoms with chronic overproduction of glucocorticoids in the adrenal cortex.Its clinical manifestations are“moon face”and“buffalo hump,”involving blood circulation,bone metabolism,and gonadal function,among others.In addition,severe trauma or burn leads to an imbalanced immune regulatory system,resulting in excessive inflammatory reactions and sepsis.Thus,an independent or cooperative regulation of multiple regulatory systems is critical in maintaining the body’s homeostasis,healthy development,and growth.展开更多
Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treat...Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treatment for peripheral nerve injuries.In this study,we first experimented an optimal scaffold material synthesis protocol,from where we selected the 10%GFD formula(10%GelMA hydrogel,recombinant human basic fibroblast growth factor and dental pulp stem cells(DPSCs))to fill a cellulose/soy protein isolate composite membrane(CSM)tube to construct a third generation of nerve regeneration conduit,CSM-GFD.Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model.After 12 week post implant surgery,at histologic level,we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers.At physical level,CSM-GFD achieved functional recovery assessed by a sciatic functional index study.In both levels,CSM-GFD performed like what gold standard,the nerve autograft,could do.Further,we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD.In conclusion,we claimed that this third-generation nerve regeneration conduit,CSM-GFD,could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.展开更多
Cell-based transplantation strategies possess great potential for spinal cord injury(SCI)repair.Basic fibroblast growth factor(bFGF)has been reported to have multiple neuro-promoting effects on developing and adult ne...Cell-based transplantation strategies possess great potential for spinal cord injury(SCI)repair.Basic fibroblast growth factor(bFGF)has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI.Human dental pulp stem cells(DPSCs)are abundant stem cells with low immune rejection,which can be considered for cell replacement therapy.The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements(5HRE)using an adeno-associated virus(AAV-5HRE-bFGF-DPSCs)in SCI repairing model.In this study,DPSCs were revealed to differentiate into CD13^(+)pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13^(+)pericytes to vascular endothelial cells.The re-attachment of CD13^(+)pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance.As a result,increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved.Thus,this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.展开更多
Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgic...Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.展开更多
Increasing evidence suggests that a cyclic adenosine monophosphate(cAMP)-dependent intracellular signal drives the process of myelination.Yet,the signal transduction underlying the action of cAMP on central nervous sy...Increasing evidence suggests that a cyclic adenosine monophosphate(cAMP)-dependent intracellular signal drives the process of myelination.Yet,the signal transduction underlying the action of cAMP on central nervous system myelination remains undefined.In the present work,we sought to determine the role of EPAC(exchange protein activated by cAMP),a downstream effector of cAMP,in the development of the myelin sheath using EPAC1 and EPAC2 double-knockout(EPACdKO)mice.The results showed an age-dependent regulatory effect of EPAC1 and EPAC2 on myelin development,as their deficiency caused more myelin sheaths in postnatal early but not late adult mice.Knockout of EPAC promoted the proliferation of oligodendrocyte precursor cells and had diverse effects on myelin-related transcription factors,which in turn increased the expression of myelin-related proteins.These results indicate that EPAC proteins are negative regulators of myelination and may be promising targets for the treatment of myelin-related diseases.展开更多
Dear Editor,Microvascular damage is a pivotal pathological factor in lower limb ischemia/reperfusion(I/R)injury.1 Excessive reactive oxygen species(ROS)formation and disrupted autophagic flux have been recognized as t...Dear Editor,Microvascular damage is a pivotal pathological factor in lower limb ischemia/reperfusion(I/R)injury.1 Excessive reactive oxygen species(ROS)formation and disrupted autophagic flux have been recognized as the critical mechanism of cellular death,2,3 especially in I/R injury.Recent investigation has displayed that fibroblast growth factor 21(FGF21)exerts a protective effect against I/R injury via transcription factor EB(TFEB)-mediated autophagy and regulation of anti-oxidative response.4 However,the promising role of FGF21 in acute lower limb I/R injury remains elusive.展开更多
The authors regret that the author(A.H.)was removed as an agreement could not be reached between the two affiliations of the author.The authors would like to apologise for any inconvenience caused.
文摘<正>Nerve repair after spinal cord injury(SCI)requires orderly growth,migration,and transmission of neuronal signals in the regenerated nerve fibers at the injury site.Neuronal apoptosis occurs at the site of injury,so a regional'barrier'forms,and the nerve fibers cannot be reconstructed in an orderly manner.
基金X.F.acknowledges the financial support from the National Natural Science Foundation of China(81830064 and 81721092)the National Key R&D Program of China(2017YFC1103300)+1 种基金J.X.acknowledges financial support from the National Natural Science Foundation of China(81722028 and 81972150)X.L.acknowledges the financial support from the National Key R&D Program of China(2017YFA0506000).
文摘Growth,development,aging,and disease occurrence in organisms,especially animals or Homo sapiens,are regulated by different regulatory systems in vivo.The nervous,endocrine,metabolic,and immune systems are the traditional biological systems essential for the growth,development,and metabolism of the body.These systems maintain a balance and precisely biologically regulate every aspect of life activities under normal circumstances.However,in abnormal situations,owing to endogenous or exogenous attack,these regulatory systems result in dysfunction,subsequently leading to illness or injury(Muggianu et al.,2018).In the classical neuroendocrine regulatory system,Cushing’s syndrome is defined as a series of abnormal clinical symptoms with chronic overproduction of glucocorticoids in the adrenal cortex.Its clinical manifestations are“moon face”and“buffalo hump,”involving blood circulation,bone metabolism,and gonadal function,among others.In addition,severe trauma or burn leads to an imbalanced immune regulatory system,resulting in excessive inflammatory reactions and sepsis.Thus,an independent or cooperative regulation of multiple regulatory systems is critical in maintaining the body’s homeostasis,healthy development,and growth.
基金supported by the National Natural Science Funding of China(81701032,81871503)the Wenzhou Science and Technology Association Project,the Wenzhou Major Scientific and Technological Innovation Key Medical and Health Project(ZY2019010)+4 种基金the Wenzhou Medical University grant(QTJ16026)Wenzhou Science and Technology Association Project,Wenzhou Basic Research Project(Y20180131)Zhejiang Province Program of the Medical and Health Science and Technology(2018KY537)Zhejiang Natural Science Foundation(LGF18C100002)Zhejiang Xinmiao Talents Program(2018R413186).
文摘Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treatment for peripheral nerve injuries.In this study,we first experimented an optimal scaffold material synthesis protocol,from where we selected the 10%GFD formula(10%GelMA hydrogel,recombinant human basic fibroblast growth factor and dental pulp stem cells(DPSCs))to fill a cellulose/soy protein isolate composite membrane(CSM)tube to construct a third generation of nerve regeneration conduit,CSM-GFD.Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model.After 12 week post implant surgery,at histologic level,we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers.At physical level,CSM-GFD achieved functional recovery assessed by a sciatic functional index study.In both levels,CSM-GFD performed like what gold standard,the nerve autograft,could do.Further,we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD.In conclusion,we claimed that this third-generation nerve regeneration conduit,CSM-GFD,could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.
基金This study was partly funded by a grant the National Natural Science Foundation of China(81802235,81871503),Zhejiang Medical and Health Science and Technology Plan Project(2021KY212),and Wenzhou Basic Science Research Plan Project(Y2020050),Advanced Postdoctoral Programs of Zhejiang(zj2019030),China Postdoctoral Science Foundation(2019M662015),CAMS Innovation Fund for Medical Sciences(2019-I2M-5-028).
文摘Cell-based transplantation strategies possess great potential for spinal cord injury(SCI)repair.Basic fibroblast growth factor(bFGF)has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI.Human dental pulp stem cells(DPSCs)are abundant stem cells with low immune rejection,which can be considered for cell replacement therapy.The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements(5HRE)using an adeno-associated virus(AAV-5HRE-bFGF-DPSCs)in SCI repairing model.In this study,DPSCs were revealed to differentiate into CD13^(+)pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13^(+)pericytes to vascular endothelial cells.The re-attachment of CD13^(+)pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance.As a result,increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved.Thus,this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.
基金supported by the National Natural Science Foundation of China(Grant Number:81874028,81702182)the Research Program of Foundation Science and Application Technology of Chongqing(Grant Number:cstc2018jcyjAX0598)Basic Medical College Foundation of Army Medical University(2019JCZX10).
文摘Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.
基金supported by the National Key Research and Development Program of Ministry of Technology and Science of China (2017YFA0104200)the National Natural Science Foundation of China (31560273,81625006,31571051,and 81571098)the Natural Science Foundation of Zhejiang Province, China (Z15C090001).
文摘Increasing evidence suggests that a cyclic adenosine monophosphate(cAMP)-dependent intracellular signal drives the process of myelination.Yet,the signal transduction underlying the action of cAMP on central nervous system myelination remains undefined.In the present work,we sought to determine the role of EPAC(exchange protein activated by cAMP),a downstream effector of cAMP,in the development of the myelin sheath using EPAC1 and EPAC2 double-knockout(EPACdKO)mice.The results showed an age-dependent regulatory effect of EPAC1 and EPAC2 on myelin development,as their deficiency caused more myelin sheaths in postnatal early but not late adult mice.Knockout of EPAC promoted the proliferation of oligodendrocyte precursor cells and had diverse effects on myelin-related transcription factors,which in turn increased the expression of myelin-related proteins.These results indicate that EPAC proteins are negative regulators of myelination and may be promising targets for the treatment of myelin-related diseases.
文摘The original version of this article unfortunately contained a mistake.The name of first author,Zhen-Zhen Gao,was wrong.It should be Zheng-Zheng Gao.
基金National Natural Science Foundation of China(81972150,82172428 To J.X.)Key scientific and technological innovation projects of Wenzhou(ZY20200023 To J.X.)+1 种基金Wenzhou Inovation Team(Growth factor drug development,No.201801)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-028).
文摘Dear Editor,Microvascular damage is a pivotal pathological factor in lower limb ischemia/reperfusion(I/R)injury.1 Excessive reactive oxygen species(ROS)formation and disrupted autophagic flux have been recognized as the critical mechanism of cellular death,2,3 especially in I/R injury.Recent investigation has displayed that fibroblast growth factor 21(FGF21)exerts a protective effect against I/R injury via transcription factor EB(TFEB)-mediated autophagy and regulation of anti-oxidative response.4 However,the promising role of FGF21 in acute lower limb I/R injury remains elusive.
文摘The authors regret that the author(A.H.)was removed as an agreement could not be reached between the two affiliations of the author.The authors would like to apologise for any inconvenience caused.
