Pain inhibition through transplantation of fetal neuronal progenitors into the injured spinal cord in rats
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摘要
Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy; nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ～70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.
Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy; nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ～70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.
Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy; nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ～70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.
引文
Abbaszadeh HA,Niknazar S,Darabi S,Ahmady Roozbahany N,Noori-Zadeh A,Ghoreishi SK,Khoramgah MS,Sadeghi Y(2018)Stem cell transplantation and functional recovery after spinal cord injury:a systematic review and meta-analysis.Anat Cell Biol 51:180-188.
Abematsu M,Smith I,Nakashima K(2006)Mechanisms of neural stem cell fate determination:extracellular cues and intracellular programs.Curr Stem Cell Res Ther 1:267-277.
Andresen SR,Biering-Sorensen F,Hagen EM,Nielsen JF,Bach FW,Finnerup NB(2016)Pain,spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.Spinal Cord 54:973-979.
Assinck P,Duncan GJ,Hilton BJ,Plemel JR,Tetzlaff W(2017)Cell transplantation therapy for spinal cord injury.Nat Neurosci 20:637-647.
Baastrup C,Finnerup NB(2008)Pharmacological management of neuropathic pain following spinal cord injury.CNS Drugs 22:455-475.
Bao CS,Li XL,Liu L,Wang B,Yang FB,Chen LG(2018)Transplantation of Human umbilical cord mesenchymal stem cells promotes functional recovery after spinal cord injury by blocking the expression of IL-7.Eur Rev Med Pharmacol Sci 22:6436-6447.
Basbaum AI,Fields HL(1978)Endogenous pain control mechanisms:review and hypothesis.Ann Neurol 4:451-462.
Basso DM,Beattie MS,Bresnahan JC,Anderson DK,Faden AI,Gruner JA,Holford TR,Hsu CY,Noble LJ,Nockels R,Perot PL,Salzman SK,Young W(1996)MASCIS evaluation of open field locomotor scores:effects of experience and teamwork on reliability.Multicenter Animal Spinal Cord Injury Study.J Neurotrauma 13:343-359.
Batista CM,Mariano ED,Onuchic F,Dale CS,Dos Santos GB,Cristante AF,Otoch JP,Teixeira MJ,Morgalla M,Lepski G(2019)Characterization of traumatic spinal cord injury model in relation to neuropathic pain in the rat.Somatosens Mot Res doi:10.1080/08990220.2018.1563537.
Berrocal YA,Almeida VW,Puentes R,Knott EP,Hechtman JF,Garland M,Pearse DD(2014)Loss of central inhibition:implications for behavioral hypersensitivity after contusive spinal cord injury in rats.Pain Res Treat 2014:178278.
Boadas-Vaello P,Castany S,Homs J,Alvarez-Perez B,Deulofeu M,Verdu E(2016)Neuroplasticity of ascending and descending pathways after somatosensory system injury:reviewing knowledge to identify neuropathic pain therapeutic targets.Spinal Cord 54:330-340.
Boroujerdi A,Zeng J,Sharp K,Kim D,Steward O,Luo ZD(2011)Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states.Pain 152:649-655.
Burke D,Lennon O,Fullen BM(2018)Quality of life after spinal cord injury:The impact of pain.Eur J Pain 22:1662-1672.
Chaplan SR,Bach FW,Pogrel JW,Chung JM,Yaksh TL(1994)Quantitative assessment of tactile allodynia in the rat paw.J Neurosci Methods 53:55-63.
Dale CS,Pagano Rde L,Paccola CC,Pinotti-Guirao T,Juliano MA,Juliano L,Giorgi R(2006)Effect of the C-terminus of murine S100A9protein on experimental nociception.Peptides 27:2794-2802.
Davies JE,Proschel C,Zhang N,Noble M,Mayer-Proschel M,Davies SJ(2008)Transplanted astrocytes derived from BMP-or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury.J Biol 7:24.
Falnikar A,Hala TJ,Poulsen DJ,Lepore AC(2016)GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury.Glia 64:396-406.
Fandel TM,Trivedi A,Nicholas CR,Zhang H,Chen J,Martinez AF,Noble-Haeusslein LJ,Kriegstein AR(2016)Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury.Cell Stem Cell 19:544-557.
Fuentealba LC,Rompani SB,Parraguez JI,Obernier K,Romero R,Cepko CL,Alvarez-Buylla A(2015)Embryonic origin of postnatal neural stem cells.Cell 161:1644-1655.
Furlanetti LL,Cordeiro JG,Cordeiro KK,Garcia JA,Winkler C,Lepski GA,Coenen VA,Nikkhah G,Dobrossy MD(2015)Continuous high-frequency stimulation of the subthalamic nucleus improves cell survival and functional recovery following dopaminergic cell transplantation in rodents.Neurorehabil Neural Repair 29:1001-1012.
Gage FH(2000)Mammalian neural stem cells.Science 287:1433-1438.
Gilron I,Baron R,Jensen T(2015)Neuropathic pain:principles of diagnosis and treatment.Mayo Clin Proc 90:532-545.
Gruner JA(1992)A monitored contusion model of spinal cord injury in the rat.J Neurotrauma 9:123-128.
Gwak YS,Hulsebosch CE,Leem JW(2017)Neuronal-glial interactions maintain chronic neuropathic pain after spinal cord injury.Neural Plast 2017:2480689.
Hatch MN,Cushing TR,Carlson GD,Chang EY(2018)Neuropathic pain and SCI:Identification and treatment strategies in the 21st century.J Neurol Sci 384:75-83.
Hofstetter CP,Holmstrom NA,Lilja JA,Schweinhardt P,Hao J,Spenger C,Wiesenfeld-Hallin Z,Kurpad SN,Frisen J,Olson L(2005)Allodynia limits the usefulness of intraspinal neural stem cell grafts;directed differentiation improves outcome.Nat Neurosci 8:346-353.
Hwang I,Hahm SC,Choi KA,Park SH,Jeong H,Yea JH,Kim J,Hong S(2016)Intrathecal transplantation of embryonic stem cell-derived spinal GABAergic neural precursor cells attenuates neuropathic pain in a spinal cord injury rat model.Cell Transplant 25:593-607.
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Kandel E,Schwartz J,Jessell T,Siegelbaum S,Hudspeth A(2012)Principles of neural science.5th ed.New York:McGraw-Hill.
Kim HJ,Park JS(2017)Usage of human mesenchymal stem cells in cellbased therapy:advantages and disadvantages.Dev Reprod 21:1-10.
Kramer JL,Minhas NK,Jutzeler CR,Erskine EL,Liu LJ,Ramer MS(2017)Neuropathic pain following traumatic spinal cord injury:Models,measurement,and mechanisms.J Neurosci Res 95:1295-1306.
Kumar R,Lim J,Mekary RA,Rattani A,Dewan MC,Sharif SY,Osorio-Fonseca E,Park KB(2018)Traumatic spinal injury:global epidemiology and worldwide volume.World Neurosurg 113:e345-363.
Lepski G,Jannes CE,Nikkhah G,Bischofberger J(2013)cAMP promotes the differentiation of neural progenitor cells in vitro via modulation of voltage-gated calcium channels.Front Cell Neurosci 7:155.
Lepski G,Jannes CE,Strauss B,Marie SK,Nikkhah G(2010)Survival and neuronal differentiation of mesenchymal stem cells transplanted into the rodent brain are dependent upon microenvironment.Tissue Eng Part A 16:2769-2782.
Lepski G,Jannes CE,Wessolleck J,Kobayashi E,Nikkhah G(2011a)Equivalent neurogenic potential of wild-type and GFP-labeled fetal-derived neural progenitor cells before and after transplantation into the rodent hippocampus.Transplantation 91:390-397.
Lepski G,Maciaczyk J,Jannes CE,Maciaczyk D,Bischofberger J,Nikkhah G(2011b)Delayed functional maturation of human neuronal progenitor cells in vitro.Mol Cell Neurosci 47:36-44.
Luo Y,Zou Y,Yang L,Liu J,Liu S,Zhou X,Zhang W,Wang T(2013)Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury.Neurosci Lett 549:103-108.
Maciaczyk J,Singec I,Maciaczyk D,Nikkhah G(2008)Combined use of BDNF,ascorbic acid,low oxygen,and prolonged differentiation time generates tyrosine hydroxylase-expressing neurons after longterm in vitro expansion of human fetal midbrain precursor cells.Exp Neurol 213:354-362.
Maciaczyk J,Singec I,Maciaczyk D,Klein A,Nikkhah G(2009)Restricted spontaneous in vitro differentiation and region-specific migration of long-term expanded fetal human neural precursor cells after transplantation into the adult rat brain.Stem Cells Dev 18:1043-1058.
Macias MY,Syring MB,Pizzi MA,Crowe MJ,Alexanian AR,Kurpad SN(2006)Pain with no gain:allodynia following neural stem cell transplantation in spinal cord injury.Exp Neurol 201:335-348.
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Abematsu M,Smith I,Nakashima K(2006)Mechanisms of neural stem cell fate determination:extracellular cues and intracellular programs.Curr Stem Cell Res Ther 1:267-277.
Andresen SR,Biering-Sorensen F,Hagen EM,Nielsen JF,Bach FW,Finnerup NB(2016)Pain,spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.Spinal Cord 54:973-979.
Assinck P,Duncan GJ,Hilton BJ,Plemel JR,Tetzlaff W(2017)Cell transplantation therapy for spinal cord injury.Nat Neurosci 20:637-647.
Baastrup C,Finnerup NB(2008)Pharmacological management of neuropathic pain following spinal cord injury.CNS Drugs 22:455-475.
Bao CS,Li XL,Liu L,Wang B,Yang FB,Chen LG(2018)Transplantation of Human umbilical cord mesenchymal stem cells promotes functional recovery after spinal cord injury by blocking the expression of IL-7.Eur Rev Med Pharmacol Sci 22:6436-6447.
Basbaum AI,Fields HL(1978)Endogenous pain control mechanisms:review and hypothesis.Ann Neurol 4:451-462.
Basso DM,Beattie MS,Bresnahan JC,Anderson DK,Faden AI,Gruner JA,Holford TR,Hsu CY,Noble LJ,Nockels R,Perot PL,Salzman SK,Young W(1996)MASCIS evaluation of open field locomotor scores:effects of experience and teamwork on reliability.Multicenter Animal Spinal Cord Injury Study.J Neurotrauma 13:343-359.
Batista CM,Mariano ED,Onuchic F,Dale CS,Dos Santos GB,Cristante AF,Otoch JP,Teixeira MJ,Morgalla M,Lepski G(2019)Characterization of traumatic spinal cord injury model in relation to neuropathic pain in the rat.Somatosens Mot Res doi:10.1080/08990220.2018.1563537.
Berrocal YA,Almeida VW,Puentes R,Knott EP,Hechtman JF,Garland M,Pearse DD(2014)Loss of central inhibition:implications for behavioral hypersensitivity after contusive spinal cord injury in rats.Pain Res Treat 2014:178278.
Boadas-Vaello P,Castany S,Homs J,Alvarez-Perez B,Deulofeu M,Verdu E(2016)Neuroplasticity of ascending and descending pathways after somatosensory system injury:reviewing knowledge to identify neuropathic pain therapeutic targets.Spinal Cord 54:330-340.
Boroujerdi A,Zeng J,Sharp K,Kim D,Steward O,Luo ZD(2011)Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states.Pain 152:649-655.
Burke D,Lennon O,Fullen BM(2018)Quality of life after spinal cord injury:The impact of pain.Eur J Pain 22:1662-1672.
Chaplan SR,Bach FW,Pogrel JW,Chung JM,Yaksh TL(1994)Quantitative assessment of tactile allodynia in the rat paw.J Neurosci Methods 53:55-63.
Dale CS,Pagano Rde L,Paccola CC,Pinotti-Guirao T,Juliano MA,Juliano L,Giorgi R(2006)Effect of the C-terminus of murine S100A9protein on experimental nociception.Peptides 27:2794-2802.
Davies JE,Proschel C,Zhang N,Noble M,Mayer-Proschel M,Davies SJ(2008)Transplanted astrocytes derived from BMP-or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury.J Biol 7:24.
Falnikar A,Hala TJ,Poulsen DJ,Lepore AC(2016)GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury.Glia 64:396-406.
Fandel TM,Trivedi A,Nicholas CR,Zhang H,Chen J,Martinez AF,Noble-Haeusslein LJ,Kriegstein AR(2016)Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury.Cell Stem Cell 19:544-557.
Fuentealba LC,Rompani SB,Parraguez JI,Obernier K,Romero R,Cepko CL,Alvarez-Buylla A(2015)Embryonic origin of postnatal neural stem cells.Cell 161:1644-1655.
Furlanetti LL,Cordeiro JG,Cordeiro KK,Garcia JA,Winkler C,Lepski GA,Coenen VA,Nikkhah G,Dobrossy MD(2015)Continuous high-frequency stimulation of the subthalamic nucleus improves cell survival and functional recovery following dopaminergic cell transplantation in rodents.Neurorehabil Neural Repair 29:1001-1012.
Gage FH(2000)Mammalian neural stem cells.Science 287:1433-1438.
Gilron I,Baron R,Jensen T(2015)Neuropathic pain:principles of diagnosis and treatment.Mayo Clin Proc 90:532-545.
Gruner JA(1992)A monitored contusion model of spinal cord injury in the rat.J Neurotrauma 9:123-128.
Gwak YS,Hulsebosch CE,Leem JW(2017)Neuronal-glial interactions maintain chronic neuropathic pain after spinal cord injury.Neural Plast 2017:2480689.
Hatch MN,Cushing TR,Carlson GD,Chang EY(2018)Neuropathic pain and SCI:Identification and treatment strategies in the 21st century.J Neurol Sci 384:75-83.
Hofstetter CP,Holmstrom NA,Lilja JA,Schweinhardt P,Hao J,Spenger C,Wiesenfeld-Hallin Z,Kurpad SN,Frisen J,Olson L(2005)Allodynia limits the usefulness of intraspinal neural stem cell grafts;directed differentiation improves outcome.Nat Neurosci 8:346-353.
Hwang I,Hahm SC,Choi KA,Park SH,Jeong H,Yea JH,Kim J,Hong S(2016)Intrathecal transplantation of embryonic stem cell-derived spinal GABAergic neural precursor cells attenuates neuropathic pain in a spinal cord injury rat model.Cell Transplant 25:593-607.
IASP(2012).IASP Terminology updated from:Merskey H,Bogduk N(1994).Classification of chronic pain.Part III:Pain terms,a current list with definitions and notes on usage.2nd ed,IASP Press,Seattle,209-214.Website:https://www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673&navItemNumber=677.
Kandel E,Schwartz J,Jessell T,Siegelbaum S,Hudspeth A(2012)Principles of neural science.5th ed.New York:McGraw-Hill.
Kim HJ,Park JS(2017)Usage of human mesenchymal stem cells in cellbased therapy:advantages and disadvantages.Dev Reprod 21:1-10.
Kramer JL,Minhas NK,Jutzeler CR,Erskine EL,Liu LJ,Ramer MS(2017)Neuropathic pain following traumatic spinal cord injury:Models,measurement,and mechanisms.J Neurosci Res 95:1295-1306.
Kumar R,Lim J,Mekary RA,Rattani A,Dewan MC,Sharif SY,Osorio-Fonseca E,Park KB(2018)Traumatic spinal injury:global epidemiology and worldwide volume.World Neurosurg 113:e345-363.
Lepski G,Jannes CE,Nikkhah G,Bischofberger J(2013)cAMP promotes the differentiation of neural progenitor cells in vitro via modulation of voltage-gated calcium channels.Front Cell Neurosci 7:155.
Lepski G,Jannes CE,Strauss B,Marie SK,Nikkhah G(2010)Survival and neuronal differentiation of mesenchymal stem cells transplanted into the rodent brain are dependent upon microenvironment.Tissue Eng Part A 16:2769-2782.
Lepski G,Jannes CE,Wessolleck J,Kobayashi E,Nikkhah G(2011a)Equivalent neurogenic potential of wild-type and GFP-labeled fetal-derived neural progenitor cells before and after transplantation into the rodent hippocampus.Transplantation 91:390-397.
Lepski G,Maciaczyk J,Jannes CE,Maciaczyk D,Bischofberger J,Nikkhah G(2011b)Delayed functional maturation of human neuronal progenitor cells in vitro.Mol Cell Neurosci 47:36-44.
Luo Y,Zou Y,Yang L,Liu J,Liu S,Zhou X,Zhang W,Wang T(2013)Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury.Neurosci Lett 549:103-108.
Maciaczyk J,Singec I,Maciaczyk D,Nikkhah G(2008)Combined use of BDNF,ascorbic acid,low oxygen,and prolonged differentiation time generates tyrosine hydroxylase-expressing neurons after longterm in vitro expansion of human fetal midbrain precursor cells.Exp Neurol 213:354-362.
Maciaczyk J,Singec I,Maciaczyk D,Klein A,Nikkhah G(2009)Restricted spontaneous in vitro differentiation and region-specific migration of long-term expanded fetal human neural precursor cells after transplantation into the adult rat brain.Stem Cells Dev 18:1043-1058.
Macias MY,Syring MB,Pizzi MA,Crowe MJ,Alexanian AR,Kurpad SN(2006)Pain with no gain:allodynia following neural stem cell transplantation in spinal cord injury.Exp Neurol 201:335-348.
Martino G,Pluchino S(2006)The therapeutic potential of neural stem cells.Nat Rev Neurosci 7:395-406.
Mehta S,Guy S,Lam T,Teasell R,Loh E(2015)Antidepressants are effective in decreasing neuropathic pain after SCI:a meta-analysis.Top Spinal Cord Inj Rehabil 21:166-173.
Meisner JG,Marsh AD,Marsh DR(2010)Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury.J Neurotrauma 27:729-737.
Miazga K,Fabczak H,Joachimiak E,Zawadzka M,Krzemien-Ojak L,Bekisz M,Bejrowska A,Jordan LM,Slawinska U(2018)Intraspinal grafting of serotonergic neurons modifies expression of genes important for functional recovery in paraplegic rats.Neural Plast2018:4232706.
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