Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke
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摘要
Soluble Nogo66 receptor-Fc protein(sNgR-Fc)enhances axonal regeneration following central nervous system injury.However,the underlying mechanisms remain unclear.In this study,we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells.The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats.The rats with photothrombotic cortical injury were randomized to receive infusion of 400μg/kg sNgR-Fc(sNgR-Fc group)or an equal volume of phosphate-buffered saline(photothrombotic cortical injury group)into the lateral ventricle for 3 days.The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining.Neurological function was evaluated with the Morris water maze test.To further examine the effects of sNgR-Fc treatment on neural progenitor cells,photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats.The animals were then given an infusion of phosphate-buffered saline(neural progenitor cells group)or sNgR-Fc(sNgR-Fc+neural progenitor cells group)into the lateral ventricle for 3 days.sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo,compared with phosphate-buffered saline,and it also induced the differentiation of neural progenitor cells into neurons.Compared with the photothrombotic cortical injury group,escape latency in the Morris water maze and neurological severity score were greatly reduced,and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group,indicating a substantial improvement in neurological function.Furthermore,compared with phosphate-buffered saline infusion,sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells.Our findings show that sNgR-Fc regulates neural progenitor cell proliferation,migration and differentiation.Therefore,sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases,The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong(approval No.4560-17)in November,2015.
Soluble Nogo66 receptor-Fc protein(sNgR-Fc)enhances axonal regeneration following central nervous system injury.However,the underlying mechanisms remain unclear.In this study,we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells.The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats.The rats with photothrombotic cortical injury were randomized to receive infusion of 400μg/kg sNgR-Fc(sNgR-Fc group)or an equal volume of phosphate-buffered saline(photothrombotic cortical injury group)into the lateral ventricle for 3 days.The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining.Neurological function was evaluated with the Morris water maze test.To further examine the effects of sNgR-Fc treatment on neural progenitor cells,photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats.The animals were then given an infusion of phosphate-buffered saline(neural progenitor cells group)or sNgR-Fc(sNgR-Fc+neural progenitor cells group)into the lateral ventricle for 3 days.sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo,compared with phosphate-buffered saline,and it also induced the differentiation of neural progenitor cells into neurons.Compared with the photothrombotic cortical injury group,escape latency in the Morris water maze and neurological severity score were greatly reduced,and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group,indicating a substantial improvement in neurological function.Furthermore,compared with phosphate-buffered saline infusion,sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells.Our findings show that sNgR-Fc regulates neural progenitor cell proliferation,migration and differentiation.Therefore,sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases,The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong(approval No.4560-17)in November,2015.
Soluble Nogo66 receptor-Fc protein(sNgR-Fc)enhances axonal regeneration following central nervous system injury.However,the underlying mechanisms remain unclear.In this study,we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells.The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats.The rats with photothrombotic cortical injury were randomized to receive infusion of 400μg/kg sNgR-Fc(sNgR-Fc group)or an equal volume of phosphate-buffered saline(photothrombotic cortical injury group)into the lateral ventricle for 3 days.The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining.Neurological function was evaluated with the Morris water maze test.To further examine the effects of sNgR-Fc treatment on neural progenitor cells,photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats.The animals were then given an infusion of phosphate-buffered saline(neural progenitor cells group)or sNgR-Fc(sNgR-Fc+neural progenitor cells group)into the lateral ventricle for 3 days.sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo,compared with phosphate-buffered saline,and it also induced the differentiation of neural progenitor cells into neurons.Compared with the photothrombotic cortical injury group,escape latency in the Morris water maze and neurological severity score were greatly reduced,and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group,indicating a substantial improvement in neurological function.Furthermore,compared with phosphate-buffered saline infusion,sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells.Our findings show that sNgR-Fc regulates neural progenitor cell proliferation,migration and differentiation.Therefore,sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases,The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong(approval No.4560-17)in November,2015.
引文
Abdesselem H,Shypitsyna A,Solis GP,Bodrikov V,Stuermer CA(2009)No Nogo66-and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve.J Neurosci 29:15489-15498.
Arvidsson A,Collin T,Kirik D,Kokaia Z,Lindvall O(2002)Neuronal replacement from endogenous precursors in the adult brain after stroke.Nat Med 8:963-970.
Buhnemann C,Scholz A,Bernreuther C,Malik CY,Braun H,Schachner M,Reymann KG,Dihne M(2006)Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats.Brain 129:3238-3248.
Cassella CR,Jagoda A(2017)Ischemic stroke:advances in diagnosis and management.Emerg Med Clin North Am 35:911-930.
Chang QY,Lin YW,Hsieh CL(2018)Acupuncture and neuroregeneration in ischemic stroke.Neural Regen Res 13:573-583.
Chau M,Deveau TC,Song M,Wei ZZ,Gu X,Yu SP,Wei L(2017)Transplantation of iPS cell-derived neural progenitors overexpressing SDF-1alpha increases regeneration and functional recovery after ischemic stroke.Oncotarget 8:97537-97553.
Daadi MM,Davis AS,Arac A,Li Z,Maag AL,Bhatnagar R,Jiang K,Sun G,Wu JC,Steinberg GK(2010)Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury.Stroke 41:516-523.
Dadwal P,Mahmud N,Sinai L,Azimi A,Fatt M,Wondisford FE,Miller FD,Morshead CM(2015)Activating endogenous neural precursor cells using metformin leads to neural repair and functional recovery in a model of childhood brain injury.Stem Cell Rep 5:166-173.
Faulkner J,Wright A(2018)Using robotic-assisted technology to improve lower-limb function in people with stroke.Clin Trials Degener Dis 3:111-114.
Feng R,Badgeley M,Mocco J,Oermann EK(2018)Deep learning guided stroke management:a review of clinical applications.J Neurointerv Surg 10:358-362.
Flippo KH,Gnanasekaran A,Perkins GA,Ajmal A,Merrill RA,Dickey AS,Taylor SS,McKnight GS,Chauhan AK,Usachev YM,Strack S(2018)AKAP1 protects from cerebral ischemic stroke by inhibiting Drp1-dependent mitochondrial fission.J Neurosci 38:8233-8242.
Frid K,Binyamin O,Fainstein N,Keller G,Ben-Hur T,Gabizon R(2018)Autologous neural progenitor cell transplantation into newborn mice modeling for E200K genetic prion disease delays disease progression.Neurobiol Aging 65:192-200.
Guo J,Zeng Y,Liang Y,Wang L,Su H,Wu W(2007)Cyclosporine affects the proliferation and differentiation of neural stem cells in culture.Neuroreport 18:863-868.
Hicks AU,Lappalainen RS,Narkilahti S,Suuronen R,Corbett D,Sivenius J,Hovatta O,Jolkkonen J(2009)Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats:cell survival and functional recovery.Eur J Neurosci 29:562-574.
Jahanbazi Jahan-Abad A,Sahab Negah S,Hosseini Ravandi H,Ghasemi S,Borhani-Haghighi M,Stummer W,Gorji A,Khaleghi Ghadiri M(2018)Human neural stem/progenitor cells derived from epileptic human brain in a self-assembling peptide nanoscaffold improve traumatic brain injury in rats.Mol Neurobiol 55:9122-9138
Kang C,Yang CY,Kim JH,Moon SK,Lee S,Park SA,Han EH,Zhang LQ(2013)The effect of continuous epidural electrical stimulation on neuronal proliferation in cerebral ischemic rats.Ann Rehabil Med37:301-310.
Kim YR,Kim HN,Ahn SM,Choi YH,Shin HK,Choi BT(2014)Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia.PLoS One 9:e90000.
Li G,Yu F,Lei T,Gao H,Li P,Sun Y,Huang H,Mu Q(2016)Bone marrow mesenchymal stem cell therapy in ischemic stroke:mechanisms of action and treatment optimization strategies.Neural Regen Res 11:1015-1024.
Li X,Su H,Fu QL,Guo J,Lee DH,So KF,Wu W(2011)Soluble NgRfusion protein modulates the proliferation of neural progenitor cells via the Notch pathway.Neurochem Res 36:2363-2372.
Lindvall O,Kokaia Z(2010)Stem cells in human neurodegenerative disorders--time for clinical translation?J Clin Invest 120:29-40.
Lu P,Wang Y,Graham L,McHale K,Gao M,Wu D,Brock J,Blesch A,Rosenzweig ES,Havton LA,Zheng B,Conner JM,Marsala M,Tuszynski MH(2012)Long-distance growth and connectivity of neural stem cells after severe spinal cord injury.Cell 150:1264-1273.
Ludwig PE,Thankam FG,Patil AA,Chamczuk AJ,Agrawal DK(2018)Brain injury and neural stem cells.Neural Regen Res 13:7-18.
Mangin G,Kubis N(2018)Cell therapy for ischemic stroke:how to turn a promising preclinical research into a successful clinical story.Stem Cell Rev doi:10.1007/s12015-018-9864-3.
Marei HE,Hasan A,Rizzi R,Althani A,Afifi N,Cenciarelli C,Caceci T,Shuaib A(2018)Potential of stem cell-based therapy for ischemic stroke.Front Neurol 9:34.
Mi S,Pepinsky RB,Cadavid D(2013)Blocking LINGO-1 as a therapy to promote CNS repair:from concept to the clinic.CNS Drugs27:493-503.
Mine Y,Tatarishvili J,Oki K,Monni E,Kokaia Z,Lindvall O(2013)Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats.Neurobiol Dis 52:191-203.
Minnerup J,Wersching H,Schilling M,Schabitz WR(2014)Analysis of early phase and subsequent phase III stroke studies of neuroprotectants:outcomes and predictors for success.Exp Transl Stroke Med 6:2.
Nakatomi H,Kuriu T,Okabe S,Yamamoto S,Hatano O,Kawahara N,Tamura A,Kirino T,Nakafuku M(2002)Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.Cell 110:429-441.
Radak D,Katsiki N,Resanovic I,Jovanovic A,Sudar-Milovanovic E,Zafirovic S,Mousad SA,Isenovic ER(2017)Apoptosis and acute brain ischemia in ischemic stroke.Curr Vasc Pharmacol 15:115-122.
Russo E,Nguyen H,Lippert T,Tuazon J,Borlongan CV,Napoli E(2018)Mitochondrial targeting as a novel therapy for stroke.Brain Circ 4:84-94.
Ryu S,Lee SH,Kim SU,Yoon BW(2016)Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.Neural Regen Res 11:298-304.
Schwab ME,Strittmatter SM(2014)Nogo limits neural plasticity and recovery from injury.Curr Opin Neurobiol 27:53-60.
Sekerdag E,Solaroglu I,Gursoy-Ozdemir Y(2018)Cell death mechanisms in stroke and novel molecular and cellular treatment options.Curr Neuropharmacol 16:1396-1415.
Tang G,Liu Y,Zhang Z,Lu Y,Wang Y,Huang J,Li Y,Chen X,Gu X,Wang Y,Yang GY(2014)Mesenchymal stem cells maintain bloodbrain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia.Stem Cells 32:3150-3162.
Tobin MK,Bonds JA,Minshall RD,Pelligrino DA,Testai FD,Lazarov O(2014)Neurogenesis and inflammation after ischemic stroke:what is known and where we go from here.J Cereb Blood Flow Metab 34:1573-1584.
Tseng KY,Anttila JE,Khodosevich K,Tuominen RK,Lindahl M,Domanskyi A,Airavaara M(2018)MANF Promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke.Mol Ther 26:238-255.
Tuo QZ,Liuyang ZY,Lei P,Yan X,Shentu YP,Liang JW,Zhou H,Pei L,Xiong Y,Hou TY,Zhou XW,Wang Q,Wang JZ,Wang XC,Liu R(2018)Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke.Cell Death Dis9:870.
Wang L,Jiang F,Li Q,He X,Ma J(2014)Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy:neuroprotective effects of combined therapy.Neural Regen Res 9:1745-1752.
Watson BD,Dietrich WD,Busto R,Wachtel MS,Ginsberg MD(1985)Induction of reproducible brain infarction by photochemically initiated thrombosis.Ann Neurol 17:497-504.
Webb RL,Kaiser EE,Jurgielewicz BJ,Spellicy S,Scoville SL,Thompson TA,Swetenburg RL,Hess DC,West FD,Stice SL(2018)Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke.Stroke 49:1248-1256.
Wu KJ,Yu S,Lee JY,Hoffer B,Wang Y(2017)Improving neurorepair in stroke brain through endogenous neurogenesis-enhancing drugs.Cell Transplant 26:1596-1600.
Zhang F,Duan X,Lu L,Zhang X,Chen M,Mao J,Cao M,Shen J(2017a)In vivo long-term tracking of neural stem cells transplanted into an acute ischemic stroke model with reporter gene-based bimodal mr and optical imaging.Cell Transplant 26:1648-1662.
Zhang G,Guo X,Chen L,Li B,Gu B,Wang H,Wu G,Kong J,Chen W,Yu Y(2018)Interferon-gamma promotes neuronal repair by transplanted neural stem cells in ischemic rats.Stem Cells Dev 27:355-366.
Zhang JJ,Zhu JJ,Hu YB,Xiang GH,Deng LC,Wu FZ,Wei XJ,Wang YH,Sun LY,Lou XQ,Shao MM,Mao M,Zhang HY,Xu YP,Zhu SP,Xiao J(2017b)Transplantation of bFGF-expressing neural stem cells promotes cell migration and functional recovery in rat brain after transient ischemic stroke.Oncotarget 8:102067-102077.
Zhang L,Cheng H,Leng MH,Pan JH,He XC,Zhang YM,Lu S,Chen H(2018)Effect of formyl peptide receptor on the differentiation of neural stem/progenitor cells into neurons.Zhongguo Zuzhi Gongcheng Yanjiu 22:107-112.
Zhang T,Yang X,Liu T,Shao J,Fu N,Yan A,Geng K,Xia W(2017c)Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice.Stem Cell Res Ther 8:248.
Zhang Y,Chiu S,Liang X,Gao F,Zhang Z,Liao S,Liang Y,Chai YH,Low DJ,Tse HF,Tergaonkar V,Lian Q(2015)Rap1-mediated nuclear factor-kappaB(NF-kappaB)activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction.Cell Death Discov 1:15007.
Zhang Z,Xu X,Xiang Z,Yu Z,Feng J,He C(2013)LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.JBiol Chem 288:12152-12160.
Zhao XH,Jin WL,Wu J,Mi S,Ju G(2008)Inactivation of glycogen synthase kinase-3beta and up-regulation of LINGO-1 are involved in LINGO-1 antagonist regulated survival of cerebellar granular neurons.Cell Mol Neurobiol 28:727-735.
Zhou Y,Zhu J,Lv Y,Song C,Ding J,Xiao M,Lu M,Hu G(2018)Kir6.2 deficiency promotes mesencephalic neural precursor cell differentiation via regulating miR-133b/GDNF in a parkinson’s disease mouse model.Mol Neurobiol 55:8550-8562.
Zhu SZ,Szeto V,Bao MH,Sun HS,Feng ZP(2018)Pharmacological approaches promoting stem cell-based therapy following ischemic stroke insults.Acta Pharmacol Sin 39:695-712.
Arvidsson A,Collin T,Kirik D,Kokaia Z,Lindvall O(2002)Neuronal replacement from endogenous precursors in the adult brain after stroke.Nat Med 8:963-970.
Buhnemann C,Scholz A,Bernreuther C,Malik CY,Braun H,Schachner M,Reymann KG,Dihne M(2006)Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats.Brain 129:3238-3248.
Cassella CR,Jagoda A(2017)Ischemic stroke:advances in diagnosis and management.Emerg Med Clin North Am 35:911-930.
Chang QY,Lin YW,Hsieh CL(2018)Acupuncture and neuroregeneration in ischemic stroke.Neural Regen Res 13:573-583.
Chau M,Deveau TC,Song M,Wei ZZ,Gu X,Yu SP,Wei L(2017)Transplantation of iPS cell-derived neural progenitors overexpressing SDF-1alpha increases regeneration and functional recovery after ischemic stroke.Oncotarget 8:97537-97553.
Daadi MM,Davis AS,Arac A,Li Z,Maag AL,Bhatnagar R,Jiang K,Sun G,Wu JC,Steinberg GK(2010)Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury.Stroke 41:516-523.
Dadwal P,Mahmud N,Sinai L,Azimi A,Fatt M,Wondisford FE,Miller FD,Morshead CM(2015)Activating endogenous neural precursor cells using metformin leads to neural repair and functional recovery in a model of childhood brain injury.Stem Cell Rep 5:166-173.
Faulkner J,Wright A(2018)Using robotic-assisted technology to improve lower-limb function in people with stroke.Clin Trials Degener Dis 3:111-114.
Feng R,Badgeley M,Mocco J,Oermann EK(2018)Deep learning guided stroke management:a review of clinical applications.J Neurointerv Surg 10:358-362.
Flippo KH,Gnanasekaran A,Perkins GA,Ajmal A,Merrill RA,Dickey AS,Taylor SS,McKnight GS,Chauhan AK,Usachev YM,Strack S(2018)AKAP1 protects from cerebral ischemic stroke by inhibiting Drp1-dependent mitochondrial fission.J Neurosci 38:8233-8242.
Frid K,Binyamin O,Fainstein N,Keller G,Ben-Hur T,Gabizon R(2018)Autologous neural progenitor cell transplantation into newborn mice modeling for E200K genetic prion disease delays disease progression.Neurobiol Aging 65:192-200.
Guo J,Zeng Y,Liang Y,Wang L,Su H,Wu W(2007)Cyclosporine affects the proliferation and differentiation of neural stem cells in culture.Neuroreport 18:863-868.
Hicks AU,Lappalainen RS,Narkilahti S,Suuronen R,Corbett D,Sivenius J,Hovatta O,Jolkkonen J(2009)Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats:cell survival and functional recovery.Eur J Neurosci 29:562-574.
Jahanbazi Jahan-Abad A,Sahab Negah S,Hosseini Ravandi H,Ghasemi S,Borhani-Haghighi M,Stummer W,Gorji A,Khaleghi Ghadiri M(2018)Human neural stem/progenitor cells derived from epileptic human brain in a self-assembling peptide nanoscaffold improve traumatic brain injury in rats.Mol Neurobiol 55:9122-9138
Kang C,Yang CY,Kim JH,Moon SK,Lee S,Park SA,Han EH,Zhang LQ(2013)The effect of continuous epidural electrical stimulation on neuronal proliferation in cerebral ischemic rats.Ann Rehabil Med37:301-310.
Kim YR,Kim HN,Ahn SM,Choi YH,Shin HK,Choi BT(2014)Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia.PLoS One 9:e90000.
Li G,Yu F,Lei T,Gao H,Li P,Sun Y,Huang H,Mu Q(2016)Bone marrow mesenchymal stem cell therapy in ischemic stroke:mechanisms of action and treatment optimization strategies.Neural Regen Res 11:1015-1024.
Li X,Su H,Fu QL,Guo J,Lee DH,So KF,Wu W(2011)Soluble NgRfusion protein modulates the proliferation of neural progenitor cells via the Notch pathway.Neurochem Res 36:2363-2372.
Lindvall O,Kokaia Z(2010)Stem cells in human neurodegenerative disorders--time for clinical translation?J Clin Invest 120:29-40.
Lu P,Wang Y,Graham L,McHale K,Gao M,Wu D,Brock J,Blesch A,Rosenzweig ES,Havton LA,Zheng B,Conner JM,Marsala M,Tuszynski MH(2012)Long-distance growth and connectivity of neural stem cells after severe spinal cord injury.Cell 150:1264-1273.
Ludwig PE,Thankam FG,Patil AA,Chamczuk AJ,Agrawal DK(2018)Brain injury and neural stem cells.Neural Regen Res 13:7-18.
Mangin G,Kubis N(2018)Cell therapy for ischemic stroke:how to turn a promising preclinical research into a successful clinical story.Stem Cell Rev doi:10.1007/s12015-018-9864-3.
Marei HE,Hasan A,Rizzi R,Althani A,Afifi N,Cenciarelli C,Caceci T,Shuaib A(2018)Potential of stem cell-based therapy for ischemic stroke.Front Neurol 9:34.
Mi S,Pepinsky RB,Cadavid D(2013)Blocking LINGO-1 as a therapy to promote CNS repair:from concept to the clinic.CNS Drugs27:493-503.
Mine Y,Tatarishvili J,Oki K,Monni E,Kokaia Z,Lindvall O(2013)Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats.Neurobiol Dis 52:191-203.
Minnerup J,Wersching H,Schilling M,Schabitz WR(2014)Analysis of early phase and subsequent phase III stroke studies of neuroprotectants:outcomes and predictors for success.Exp Transl Stroke Med 6:2.
Nakatomi H,Kuriu T,Okabe S,Yamamoto S,Hatano O,Kawahara N,Tamura A,Kirino T,Nakafuku M(2002)Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.Cell 110:429-441.
Radak D,Katsiki N,Resanovic I,Jovanovic A,Sudar-Milovanovic E,Zafirovic S,Mousad SA,Isenovic ER(2017)Apoptosis and acute brain ischemia in ischemic stroke.Curr Vasc Pharmacol 15:115-122.
Russo E,Nguyen H,Lippert T,Tuazon J,Borlongan CV,Napoli E(2018)Mitochondrial targeting as a novel therapy for stroke.Brain Circ 4:84-94.
Ryu S,Lee SH,Kim SU,Yoon BW(2016)Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.Neural Regen Res 11:298-304.
Schwab ME,Strittmatter SM(2014)Nogo limits neural plasticity and recovery from injury.Curr Opin Neurobiol 27:53-60.
Sekerdag E,Solaroglu I,Gursoy-Ozdemir Y(2018)Cell death mechanisms in stroke and novel molecular and cellular treatment options.Curr Neuropharmacol 16:1396-1415.
Tang G,Liu Y,Zhang Z,Lu Y,Wang Y,Huang J,Li Y,Chen X,Gu X,Wang Y,Yang GY(2014)Mesenchymal stem cells maintain bloodbrain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia.Stem Cells 32:3150-3162.
Tobin MK,Bonds JA,Minshall RD,Pelligrino DA,Testai FD,Lazarov O(2014)Neurogenesis and inflammation after ischemic stroke:what is known and where we go from here.J Cereb Blood Flow Metab 34:1573-1584.
Tseng KY,Anttila JE,Khodosevich K,Tuominen RK,Lindahl M,Domanskyi A,Airavaara M(2018)MANF Promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke.Mol Ther 26:238-255.
Tuo QZ,Liuyang ZY,Lei P,Yan X,Shentu YP,Liang JW,Zhou H,Pei L,Xiong Y,Hou TY,Zhou XW,Wang Q,Wang JZ,Wang XC,Liu R(2018)Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke.Cell Death Dis9:870.
Wang L,Jiang F,Li Q,He X,Ma J(2014)Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy:neuroprotective effects of combined therapy.Neural Regen Res 9:1745-1752.
Watson BD,Dietrich WD,Busto R,Wachtel MS,Ginsberg MD(1985)Induction of reproducible brain infarction by photochemically initiated thrombosis.Ann Neurol 17:497-504.
Webb RL,Kaiser EE,Jurgielewicz BJ,Spellicy S,Scoville SL,Thompson TA,Swetenburg RL,Hess DC,West FD,Stice SL(2018)Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke.Stroke 49:1248-1256.
Wu KJ,Yu S,Lee JY,Hoffer B,Wang Y(2017)Improving neurorepair in stroke brain through endogenous neurogenesis-enhancing drugs.Cell Transplant 26:1596-1600.
Zhang F,Duan X,Lu L,Zhang X,Chen M,Mao J,Cao M,Shen J(2017a)In vivo long-term tracking of neural stem cells transplanted into an acute ischemic stroke model with reporter gene-based bimodal mr and optical imaging.Cell Transplant 26:1648-1662.
Zhang G,Guo X,Chen L,Li B,Gu B,Wang H,Wu G,Kong J,Chen W,Yu Y(2018)Interferon-gamma promotes neuronal repair by transplanted neural stem cells in ischemic rats.Stem Cells Dev 27:355-366.
Zhang JJ,Zhu JJ,Hu YB,Xiang GH,Deng LC,Wu FZ,Wei XJ,Wang YH,Sun LY,Lou XQ,Shao MM,Mao M,Zhang HY,Xu YP,Zhu SP,Xiao J(2017b)Transplantation of bFGF-expressing neural stem cells promotes cell migration and functional recovery in rat brain after transient ischemic stroke.Oncotarget 8:102067-102077.
Zhang L,Cheng H,Leng MH,Pan JH,He XC,Zhang YM,Lu S,Chen H(2018)Effect of formyl peptide receptor on the differentiation of neural stem/progenitor cells into neurons.Zhongguo Zuzhi Gongcheng Yanjiu 22:107-112.
Zhang T,Yang X,Liu T,Shao J,Fu N,Yan A,Geng K,Xia W(2017c)Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice.Stem Cell Res Ther 8:248.
Zhang Y,Chiu S,Liang X,Gao F,Zhang Z,Liao S,Liang Y,Chai YH,Low DJ,Tse HF,Tergaonkar V,Lian Q(2015)Rap1-mediated nuclear factor-kappaB(NF-kappaB)activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction.Cell Death Discov 1:15007.
Zhang Z,Xu X,Xiang Z,Yu Z,Feng J,He C(2013)LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.JBiol Chem 288:12152-12160.
Zhao XH,Jin WL,Wu J,Mi S,Ju G(2008)Inactivation of glycogen synthase kinase-3beta and up-regulation of LINGO-1 are involved in LINGO-1 antagonist regulated survival of cerebellar granular neurons.Cell Mol Neurobiol 28:727-735.
Zhou Y,Zhu J,Lv Y,Song C,Ding J,Xiao M,Lu M,Hu G(2018)Kir6.2 deficiency promotes mesencephalic neural precursor cell differentiation via regulating miR-133b/GDNF in a parkinson’s disease mouse model.Mol Neurobiol 55:8550-8562.
Zhu SZ,Szeto V,Bao MH,Sun HS,Feng ZP(2018)Pharmacological approaches promoting stem cell-based therapy following ischemic stroke insults.Acta Pharmacol Sin 39:695-712.