Metformin,a first-line drug for type-2 diabetes,has been shown to improve locomotor recovery after spinal cord injury.However,there are studies reporting no beneficial effect.Recently,we found that high dose of metfor...Metformin,a first-line drug for type-2 diabetes,has been shown to improve locomotor recovery after spinal cord injury.However,there are studies reporting no beneficial effect.Recently,we found that high dose of metformin(200 mg/kg,intraperitoneal)and acute phase administration(immediately after injury)led to increased mortality and limited locomotor function recovery.Consequently,we used a lower dose(100 mg/kg,i.p.)metformin in mice,and compared the effect of immediate administration after spinal cord injury(acute phase)with that of administration at 3 days post-injury(subacute phase).Our data showed that metformin treatment starting at the subacute phase significantly improved mouse locomotor function evaluated by Basso Mouse Scale(BMS)scoring.Immunohistochemical studies also revealed significant inhibitions of microglia/macrophage activation and astrogliosis at the lesion site.Furthermore,metformin treatment at the subacute phase reduced neutrophil infiltration.These changes were in parallel with the increased survival rate of spinal neurons in animals treated with metformin.These findings suggest that low-dose metformin treatment for subacute spinal cord injury can effectively improve the functional recovery possibly through anti-inflammation and neuroprotection.This study was approved by the Institute Animal Care and Use Committee at the University of Texas Medical Branch(approval No.1008041C)in 2010.展开更多
Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden.Exosomes,especially those derived from mesenchymal stem cells(MSCs),are pro...Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden.Exosomes,especially those derived from mesenchymal stem cells(MSCs),are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural regeneration.In this study,we reported the differentiation of human adipose derived MSCs(hADMSCs)towards the Schwann cell(SC)phenotype(hADMSC-SCs)and then isolated exosomes from hADMSCs with and without differentiation(i.e.,dExo vs uExo).We assessed and compared the effects of uExo and dExo on antioxidative,angiogenic,anti-inflammatory,and axon growth promoting properties by using various peripheral nerve-related cells.Our results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors,compared to hADMSCs without differentiation.The dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and angiogenesis.Compared to uExo,dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem cells.Furthermore,microRNA(miRNA)sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA signature.Many more miRNAs were identified in dExo than in uExo.Several upregulated miRNAs,like miRNA-132-3p and miRNA-199b-5p,were highly related to neuroprotection,anti-inflammation,and angiogenesis.The dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.展开更多
基金supported by a grant from The Institute for Rehabilitation and Research Foundation,No.MC018-112(to PW)John S.Dunn Foundation,No.18168(to PW)+2 种基金the National Natural Science foundation of China,Nos.81620108018(to SQF),81930070(to SQF),82072439(to GZN)Tianjin Key Research and Development Plan,Key Projects For Science and Technology Support of China,No.19YFZCSY00660(to SQF)the National Key R&D Program of China,No.2019YFA0112100(to SQF).
文摘Metformin,a first-line drug for type-2 diabetes,has been shown to improve locomotor recovery after spinal cord injury.However,there are studies reporting no beneficial effect.Recently,we found that high dose of metformin(200 mg/kg,intraperitoneal)and acute phase administration(immediately after injury)led to increased mortality and limited locomotor function recovery.Consequently,we used a lower dose(100 mg/kg,i.p.)metformin in mice,and compared the effect of immediate administration after spinal cord injury(acute phase)with that of administration at 3 days post-injury(subacute phase).Our data showed that metformin treatment starting at the subacute phase significantly improved mouse locomotor function evaluated by Basso Mouse Scale(BMS)scoring.Immunohistochemical studies also revealed significant inhibitions of microglia/macrophage activation and astrogliosis at the lesion site.Furthermore,metformin treatment at the subacute phase reduced neutrophil infiltration.These changes were in parallel with the increased survival rate of spinal neurons in animals treated with metformin.These findings suggest that low-dose metformin treatment for subacute spinal cord injury can effectively improve the functional recovery possibly through anti-inflammation and neuroprotection.This study was approved by the Institute Animal Care and Use Committee at the University of Texas Medical Branch(approval No.1008041C)in 2010.
基金supported by Mary&Dick Holland Regenerative Medicine Program start-up grantMary&Dick Holland Regenerative Medicine Program pilot project grant+1 种基金University of Nebraska Collaboration Initiative Grant,NIH(R21AR078439)(B.D.)UNL and UNMC Sciences,Engineering,and Medicine Initiative funding(B.D.and G.H.)。
文摘Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden.Exosomes,especially those derived from mesenchymal stem cells(MSCs),are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural regeneration.In this study,we reported the differentiation of human adipose derived MSCs(hADMSCs)towards the Schwann cell(SC)phenotype(hADMSC-SCs)and then isolated exosomes from hADMSCs with and without differentiation(i.e.,dExo vs uExo).We assessed and compared the effects of uExo and dExo on antioxidative,angiogenic,anti-inflammatory,and axon growth promoting properties by using various peripheral nerve-related cells.Our results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors,compared to hADMSCs without differentiation.The dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and angiogenesis.Compared to uExo,dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem cells.Furthermore,microRNA(miRNA)sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA signature.Many more miRNAs were identified in dExo than in uExo.Several upregulated miRNAs,like miRNA-132-3p and miRNA-199b-5p,were highly related to neuroprotection,anti-inflammation,and angiogenesis.The dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.
