人多能干细胞向多巴胺能神经元分化:异质性的安全风险
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摘要
背景:人多能干细胞源神经细胞移植治疗帕金森病的研究已经取得极大进展,进入了亚临床研究阶段,但依然有许多问题亟待解决,其中一个问题是分化的异质性,这种异质性可以引起移植后宿主体内肿瘤形成、异动症的发生,给患者带来了潜在的、不可预估的安全风险。目的:总结人多能干细胞分化为多巴胺能神经元的现状、分化方案设计的原理、诱导流程和异质性分化的研究现状,为其移植治疗实现临床转化奠定理论基础。方法:英文检索词为"iPSC AND Parkinson’s Disease,Induced pluripotent stem cells AND Parkinson’s Disease,ES cells AND Parkinson’s Disease,Embryonic stem cells AND Parkinson’s Disease,Pluripotent stem cells AND Parkinson’s Disease",中文检索词为"多能干细胞AND帕金森病,诱导多能干细胞AND帕金森病,胚胎干细胞AND帕金森病",由第一作者检索1980至2018年PubMed数据库、中文中国知网数据库和万方数据库,查阅近年诱导性多能干细胞源神经元移植治疗帕金森病的相关文献,最终保留46篇文献进行总结。结果与结论:多能干细胞应用各种不同体外诱导分化方案,可诱导分化为A9多巴胺能神经元,移植后可以促进帕金森病模型动物的行为学及肢体功能的恢复。然而目前的分化方案产物中除了可以分化为A9多巴胺能神经元外,还包括A10多巴胺能神经元、5-羟色胺能神经元等不同的神经元,尚无一种分化方案可以达到均一性分化。优化多能干细胞体外诱导分化条件,同质性分化为A9多巴胺能神经元可以进一步改善帕金森病模型动物的行为学表现,促进该细胞疗法的临床转化。
BACKGROUND: The transplantation of human pluripotent stem cell-derived nerve cells for the treatment of Parkinson's disease has made great progress and the relevant research is at the subclinical stage. However, there are still many problems to be solved. As one of the existing problems, heterogeneity of differentiation can cause tumor formation and dyskinesia in the host after transplantation, which brings potential and unpredictable risks to patients. OBJECTIVE: To summarize the current status of human pluripotent stem cells differentiated into dopaminergic neurons, the principle and process of differentiation design, the induction process and the research status of heterogeneous differentiation, laying a theoretical foundation for the clinical transformation of transplantation therapy. METHODS: The keywords were "iPSC AND Parkinson's disease, induced pluripotent stem cells AND Parkinson's disease, ES cells AND Parkinson's disease, embryonic stem cells AND Parkinson's disease, pluripotent stem cells AND Parkinson's Disease" in English and Chinese, respectively. Relevant articles published from 1980 to 2018 were retrieved by the first author in the PubMed, CNKI, and WanFang. Literature addressing the treatment of Parkinson's disease with induced pluripotent stem cell-derived neurons in recent years was reviewed, and finally 46 articles were retained. RESULTS AND CONCLUSION: A variety of induction differentiation protocols can be used to induce the differentiation of pluripotent stem cells into A9 dopaminergic neurons. Cell transplantation can promote the behavioral and limb function recovery of different Parkinson's disease models. However, in addition to the differentiation of A9 dopaminergic neurons, the current differentiation protocol products include different neurons such as A10 dopaminergic neurons and serotonergic neurons. There is no differentiation scheme that can achieve uniform differentiation. Further optimizing the differentiation conditions of human pluripotent stem cells in vitro and homogenizing differentiation into A9 dopaminergic neurons may further improve the behavioral performance of Parkinson's disease model animals and promote the clinical transformation of the cell therapy.
BACKGROUND: The transplantation of human pluripotent stem cell-derived nerve cells for the treatment of Parkinson's disease has made great progress and the relevant research is at the subclinical stage. However, there are still many problems to be solved. As one of the existing problems, heterogeneity of differentiation can cause tumor formation and dyskinesia in the host after transplantation, which brings potential and unpredictable risks to patients. OBJECTIVE: To summarize the current status of human pluripotent stem cells differentiated into dopaminergic neurons, the principle and process of differentiation design, the induction process and the research status of heterogeneous differentiation, laying a theoretical foundation for the clinical transformation of transplantation therapy. METHODS: The keywords were "iPSC AND Parkinson's disease, induced pluripotent stem cells AND Parkinson's disease, ES cells AND Parkinson's disease, embryonic stem cells AND Parkinson's disease, pluripotent stem cells AND Parkinson's Disease" in English and Chinese, respectively. Relevant articles published from 1980 to 2018 were retrieved by the first author in the PubMed, CNKI, and WanFang. Literature addressing the treatment of Parkinson's disease with induced pluripotent stem cell-derived neurons in recent years was reviewed, and finally 46 articles were retained. RESULTS AND CONCLUSION: A variety of induction differentiation protocols can be used to induce the differentiation of pluripotent stem cells into A9 dopaminergic neurons. Cell transplantation can promote the behavioral and limb function recovery of different Parkinson's disease models. However, in addition to the differentiation of A9 dopaminergic neurons, the current differentiation protocol products include different neurons such as A10 dopaminergic neurons and serotonergic neurons. There is no differentiation scheme that can achieve uniform differentiation. Further optimizing the differentiation conditions of human pluripotent stem cells in vitro and homogenizing differentiation into A9 dopaminergic neurons may further improve the behavioral performance of Parkinson's disease model animals and promote the clinical transformation of the cell therapy.
引文
[1]Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-1601.
[2]Chaudhuri KR, Healy DG, Schapira AH, et al. Non-motor symptoms of Parkinson’s disease:diagnosis and management. Lancet Neurol. 2006;5(3):235-245.
[3]Codrich M, Bertuzzi M, Russo R, et al. Neuronal hemoglobin affects dopaminergic cells’ response to stress. Cell Death Dis.2017;8(1):e2538.
[4]中华医学会神经病学分会帕金森病及运动障碍学组.中国帕金森病的诊断标准(2016版)[J].中华神经科杂志, 2016,49(4):268-271.
[5]Kirkeby A, Parmar M, Barker RA. Strategies for bringing stem cell-derived dopamine neurons to the clinic:A European approach(STEM-PD). Prog Brain Res. 2017;230:165-190.
[6]Udd M, Lyytinen J, Eerola-Rautio J, et al. Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease. Brain Behav. 2017;7(7):e00737.
[7]Suarez-Cedeno G, Suescun J, Schiess MC. Earlier Intervention with Deep Brain Stimulation for Parkinson's Disease. Parkinsons Dis. 2017;2017:9358153.
[8]Virhammar J, Nyholm D. Levodopa-carbidopa enteral suspension in advanced Parkinson's disease:clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(3):171-187.
[9]Tillmann AC, Andrade A, Swarowsky A, et al. Brazilian Samba Protocol for Individuals With Parkinson's Disease:A Clinical Non-Randomized Study. JMIR Res Protoc. 2017;6(7):e129.
[10]Li W, Englund E, Widner H, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016;113(23):6544-6549.
[11]Xia N, Fang F, Zhang P, et al. A Knockin Reporter Allows Purification and Characterization of mDA Neurons from Heterogeneous Populations. Cell Rep. 2017;18(10):2533-2546.
[12]Fox IJ, Daley GQ, Goldman SA, et al. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science. 2014;345(6199):1247391.
[13]Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011;8(3):267-280.
[14]王昱凯,周琪,胡宝洋.人胚胎干细胞来源多巴胺祖细胞治疗帕金森病猴[J].生命科学,2016(8):902-906.
[15]Kikuchi T, Morizane A, Doi D, et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. J Parkinsons Dis. 2011;1(4):395-412.
[16]Kirkeby A, Grealish S, Wolf DA, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1(6):703-714.
[17]Nolbrant S, Heuer A, Parmar M, et al. Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 2017;12(9):1962-1979.
[18]Zhao Z, Ma Y, Chen Z, et al. Effects of Feeder Cells on Dopaminergic Differentiation of Human Embryonic Stem Cells.Front Cell Neurosci. 2016;10:291.
[19]彭雅南,胡兰,王埮,等.人胚胎干细胞源多巴胺能神经元的功能性分化[J].中国组织工程研究,2017,21(33):5360-5368.
[20]Kirkeby A, Nolbrant S, Tiklova K, et al. Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.Cell Stem Cell. 2017;20(1):135-148.
[21]Doi D, Samata B, Katsukawa M, et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation.Stem Cell Reports. 2014;2(3):337-350.
[22]Grealish S, Diguet E, Kirkeby A, et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. Cell Stem Cell. 2014;15(5):653-665.
[23]Jessell TM. Neuronal specification in the spinal cord:inductive signals and transcriptional codes. Nat Rev Genet.2000;1(1):20-29.
[24]Arenas E, Denham M, Villaescusa JC. How to make a midbrain dopaminergic neuron. Development. 2015;142(11):1918-1936.
[25]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review. Cell Signal.2011;23(4):609-620.
[26]Ji EH, Kim J. SoxD Transcription Factors:Multifaceted Players of Neural Development. Int J Stem Cells. 2016;9(1):3-8.
[27]Panman L, Papathanou M, Laguna A, et al. Sox6 and Otx2control the specification of substantia nigra and ventral tegmental area dopamine neurons. Cell Rep. 2014;8(4):1018-1025.
[28]Ebrahimi-Fakhari D, Maas B, Haneke C, et al. Disruption of SOX6 is associated with a rapid-onset dopa-responsive movement disorder, delayed development, and dysmorphic features. Pediatr Neurol. 2015;52(1):115-118.
[29]Kriks S, Shim JW, Piao J, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480(7378):547-551.
[30]Veenvliet JV, Dos Santos MT, Kouwenhoven WM, et al.Specification of dopaminergic subsets involves interplay of En1 and Pitx3. Development. 2013;140(16):3373-3384.
[31]Memic F, Knoflach V, Morarach K, et al. Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System.Gastroenterology. 2018;154(3):624-636.
[32]Jovanovic VM, Salti A, Tilleman H, et al. BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons In Vivo and in Human Induced Pluripotent and Neural Stem Cells. J Neurosci. 2018;38(7):1662-1676.
[33]Tao Y, Zhang SC. Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell. 2016;19(5):573-586.
[34]Smidt MP. Molecular Programming of Mesodiencephalic Dopaminergic Neuronal Subsets. Front Neuroanat. 2017;11:59.
[35]Mesman S, von Oerthel L, Smidt MP. Mesodiencephalic dopaminergic neuronal differentiation does not involve GLI2A-mediated SHH-signaling and is under the direct influence of canonical WNT signaling. PLoS One. 2014;9(5):e97926.
[36]Sánchez-Danés A, Consiglio A, Richaud Y, et al. Efficient generation of A9 midbrain dopaminergic neurons by lentiviral delivery of LMX1A in human embryonic stem cells and induced pluripotent stem cells. Hum Gene Ther. 2012;23(1):56-69.
[37]Xi J, Liu Y, Liu H, et al. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells.2012;30(8):1655-1663.
[38]Nishimura K, Takahashi J. Therapeutic application of stem cell technology toward the treatment of Parkinson's disease.Biol Pharm Bull. 2013;36(2):171-175.
[39]Samata B, Doi D, Nishimura K, et al. Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun. 2016;7:13097.
[40]Kee N, Volakakis N, Kirkeby A, et al. Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages. Cell Stem Cell. 2017;20(1):29-40.
[41]Niclis JC, Gantner CW, Hunt CPJ, et al. A PITX3-EGFP Reporter Line Reveals Connectivity of Dopamine and Non-dopamine Neuronal Subtypes in Grafts Generated from Human Embryonic Stem Cells. Stem Cell Reports. 2017;9(3):868-882.
[42]Sundberg M, Bogetofte H, Lawson T, et al. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.Stem Cells. 2013;31(8):1548-1562.
[43]Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med. 2010;2(38):38ra46.
[44]Fasano CA, Chambers SM, Lee G, et al. Efficient derivation of functional floor plate tissue from human embryonic stem cells.Cell Stem Cell. 2010;6(4):336-347.
[45]Andersson ER, SaltóC, Villaescusa JC, et al. Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells. Proc Natl Acad Sci U S A. 2013;110(7):E602-610.
[46]Lu J, Zhong X, Liu H, et al. Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol. 2016;34(1):89-94.
[2]Chaudhuri KR, Healy DG, Schapira AH, et al. Non-motor symptoms of Parkinson’s disease:diagnosis and management. Lancet Neurol. 2006;5(3):235-245.
[3]Codrich M, Bertuzzi M, Russo R, et al. Neuronal hemoglobin affects dopaminergic cells’ response to stress. Cell Death Dis.2017;8(1):e2538.
[4]中华医学会神经病学分会帕金森病及运动障碍学组.中国帕金森病的诊断标准(2016版)[J].中华神经科杂志, 2016,49(4):268-271.
[5]Kirkeby A, Parmar M, Barker RA. Strategies for bringing stem cell-derived dopamine neurons to the clinic:A European approach(STEM-PD). Prog Brain Res. 2017;230:165-190.
[6]Udd M, Lyytinen J, Eerola-Rautio J, et al. Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease. Brain Behav. 2017;7(7):e00737.
[7]Suarez-Cedeno G, Suescun J, Schiess MC. Earlier Intervention with Deep Brain Stimulation for Parkinson's Disease. Parkinsons Dis. 2017;2017:9358153.
[8]Virhammar J, Nyholm D. Levodopa-carbidopa enteral suspension in advanced Parkinson's disease:clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(3):171-187.
[9]Tillmann AC, Andrade A, Swarowsky A, et al. Brazilian Samba Protocol for Individuals With Parkinson's Disease:A Clinical Non-Randomized Study. JMIR Res Protoc. 2017;6(7):e129.
[10]Li W, Englund E, Widner H, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016;113(23):6544-6549.
[11]Xia N, Fang F, Zhang P, et al. A Knockin Reporter Allows Purification and Characterization of mDA Neurons from Heterogeneous Populations. Cell Rep. 2017;18(10):2533-2546.
[12]Fox IJ, Daley GQ, Goldman SA, et al. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science. 2014;345(6199):1247391.
[13]Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011;8(3):267-280.
[14]王昱凯,周琪,胡宝洋.人胚胎干细胞来源多巴胺祖细胞治疗帕金森病猴[J].生命科学,2016(8):902-906.
[15]Kikuchi T, Morizane A, Doi D, et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. J Parkinsons Dis. 2011;1(4):395-412.
[16]Kirkeby A, Grealish S, Wolf DA, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1(6):703-714.
[17]Nolbrant S, Heuer A, Parmar M, et al. Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 2017;12(9):1962-1979.
[18]Zhao Z, Ma Y, Chen Z, et al. Effects of Feeder Cells on Dopaminergic Differentiation of Human Embryonic Stem Cells.Front Cell Neurosci. 2016;10:291.
[19]彭雅南,胡兰,王埮,等.人胚胎干细胞源多巴胺能神经元的功能性分化[J].中国组织工程研究,2017,21(33):5360-5368.
[20]Kirkeby A, Nolbrant S, Tiklova K, et al. Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson's Disease.Cell Stem Cell. 2017;20(1):135-148.
[21]Doi D, Samata B, Katsukawa M, et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation.Stem Cell Reports. 2014;2(3):337-350.
[22]Grealish S, Diguet E, Kirkeby A, et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. Cell Stem Cell. 2014;15(5):653-665.
[23]Jessell TM. Neuronal specification in the spinal cord:inductive signals and transcriptional codes. Nat Rev Genet.2000;1(1):20-29.
[24]Arenas E, Denham M, Villaescusa JC. How to make a midbrain dopaminergic neuron. Development. 2015;142(11):1918-1936.
[25]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review. Cell Signal.2011;23(4):609-620.
[26]Ji EH, Kim J. SoxD Transcription Factors:Multifaceted Players of Neural Development. Int J Stem Cells. 2016;9(1):3-8.
[27]Panman L, Papathanou M, Laguna A, et al. Sox6 and Otx2control the specification of substantia nigra and ventral tegmental area dopamine neurons. Cell Rep. 2014;8(4):1018-1025.
[28]Ebrahimi-Fakhari D, Maas B, Haneke C, et al. Disruption of SOX6 is associated with a rapid-onset dopa-responsive movement disorder, delayed development, and dysmorphic features. Pediatr Neurol. 2015;52(1):115-118.
[29]Kriks S, Shim JW, Piao J, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480(7378):547-551.
[30]Veenvliet JV, Dos Santos MT, Kouwenhoven WM, et al.Specification of dopaminergic subsets involves interplay of En1 and Pitx3. Development. 2013;140(16):3373-3384.
[31]Memic F, Knoflach V, Morarach K, et al. Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System.Gastroenterology. 2018;154(3):624-636.
[32]Jovanovic VM, Salti A, Tilleman H, et al. BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons In Vivo and in Human Induced Pluripotent and Neural Stem Cells. J Neurosci. 2018;38(7):1662-1676.
[33]Tao Y, Zhang SC. Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell. 2016;19(5):573-586.
[34]Smidt MP. Molecular Programming of Mesodiencephalic Dopaminergic Neuronal Subsets. Front Neuroanat. 2017;11:59.
[35]Mesman S, von Oerthel L, Smidt MP. Mesodiencephalic dopaminergic neuronal differentiation does not involve GLI2A-mediated SHH-signaling and is under the direct influence of canonical WNT signaling. PLoS One. 2014;9(5):e97926.
[36]Sánchez-Danés A, Consiglio A, Richaud Y, et al. Efficient generation of A9 midbrain dopaminergic neurons by lentiviral delivery of LMX1A in human embryonic stem cells and induced pluripotent stem cells. Hum Gene Ther. 2012;23(1):56-69.
[37]Xi J, Liu Y, Liu H, et al. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells.2012;30(8):1655-1663.
[38]Nishimura K, Takahashi J. Therapeutic application of stem cell technology toward the treatment of Parkinson's disease.Biol Pharm Bull. 2013;36(2):171-175.
[39]Samata B, Doi D, Nishimura K, et al. Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun. 2016;7:13097.
[40]Kee N, Volakakis N, Kirkeby A, et al. Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages. Cell Stem Cell. 2017;20(1):29-40.
[41]Niclis JC, Gantner CW, Hunt CPJ, et al. A PITX3-EGFP Reporter Line Reveals Connectivity of Dopamine and Non-dopamine Neuronal Subtypes in Grafts Generated from Human Embryonic Stem Cells. Stem Cell Reports. 2017;9(3):868-882.
[42]Sundberg M, Bogetofte H, Lawson T, et al. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.Stem Cells. 2013;31(8):1548-1562.
[43]Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med. 2010;2(38):38ra46.
[44]Fasano CA, Chambers SM, Lee G, et al. Efficient derivation of functional floor plate tissue from human embryonic stem cells.Cell Stem Cell. 2010;6(4):336-347.
[45]Andersson ER, SaltóC, Villaescusa JC, et al. Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells. Proc Natl Acad Sci U S A. 2013;110(7):E602-610.
[46]Lu J, Zhong X, Liu H, et al. Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol. 2016;34(1):89-94.
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