Human Clinical-Grade Parthenogenetic ESC-Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson's Disease
Yu-Kai Wang, Wan-Wan Zhu, Meng-Hua Wu, Yi-Hui Wu, Zheng-Xin Liu, Ling-Min Liang, Chao Sheng, Jie Hao, Liu Wang, Wei Li, Qi Zhou, Bao-Yang Hu, Yu-Kai Wang, Wan-Wan Zhu, Meng-Hua Wu, Yi-Hui Wu, Zheng-Xin Liu, Ling-Min Liang, Chao Sheng, Jie Hao, Liu Wang, Wei Li, Qi Zhou, Bao-Yang Hu
Abstract
Clinical application of stem cell derivatives requires clinical-grade cells and sufficient preclinical proof of safety and efficacy, preferably in primates. We previously successfully established a clinical-grade human parthenogenetic embryonic stem cell (hPESC) line, but the suitability of its subtype-specific progenies for therapy is not clear. Here, we compared the function of clinical-grade hPESC-derived midbrain dopaminergic (DA) neurons in two canonical protocols in a primate Parkinson's disease (PD) model. We found that the grafts did not form tumors and produced variable but apparent behavioral improvement for at least 24 months in most monkeys in both groups. In addition, a slight DA increase in the striatum correlates with significant functional improvement. These results demonstrated that clinical-grade hPESCs can serve as a reliable source of cells for PD treatment. Our proof-of-concept findings provide preclinical data for China's first ESC-based phase I/IIa clinical study of PD (ClinicalTrials.gov number NCT03119636).
Keywords: Parkinson's disease; cell therapy; dopaminergic neuron; embryonic stem cell; monkey; nonhuman primate.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
References
- Brownell A.L., Jenkins B.G., Elmaleh D.R., Deacon T.W., Spealman R.D., Isacson O. Combined PET/MRS brain studies show dynamic and long-term physiological changes in a primate model of Parkinson disease. Nat. Med. 1998;4:1308–1312.
- Chambers S.M., Fasano C.A., Papapetrou E.P., Tomishima M., Sadelain M., Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 2009;27:275–280.
- Ding F., Luan L., Ai Y., Walton A., Gerhardt G.A., Gash D.M., Grondin R., Zhang Z. Development of a stable, early stage unilateral model of Parkinson's disease in middle-aged rhesus monkeys. Exp. Neurol. 2008;212:431–439.
- Doi D., Morizane A., Kikuchi T., Onoe H., Hayashi T., Kawasaki T., Motono M., Sasai Y., Saiki H., Gomi M. Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease. Stem Cells. 2012;30:935–945.
- Emborg M.E., Shin P., Roitberg B., Sramek J.G., Chu Y., Stebbins G.T., Hamilton J.S., Suzdak P.D., Steiner J.P., Kordower J.H. Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys. Exp. Neurol. 2001;168:171–182.
- Emborg M.E., Ebert A.D., Moirano J., Peng S., Suzuki M., Capowski E., Joers V., Roitberg B.Z., Aebischer P., Svendsen C.N. GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys. Cell Transplant. 2008;17:383–395.
- Emborg M.E., Liu Y., Xi J., Zhang X., Yin Y., Lu J., Joers V., Swanson C., Holden J.E., Zhang S.C. Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain. Cell Rep. 2013;3:646–650.
- Emborg M.E., Zhang Z., Joers V., Brunner K., Bondarenko V., Ohshima S., Zhang S.C. Intracerebral transplantation of differentiated human embryonic stem cells to hemiparkinsonian monkeys. Cell Transplant. 2013;22:831–838.
- Espejel S., Eckardt S., Harbell J., Roll G.R., McLaughlin K.J., Willenbring H. Brief report: parthenogenetic embryonic stem cells are an effective cell source for therapeutic liver repopulation. Stem Cells. 2014;32:1983–1988.
- Fink D.W. FDA regulation of stem cell-based products. Science. 2009;324:1662–1663.
- Freed C.R., Breeze R.E., Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 2001;345:146. author reply 147.
- Ghosh A. Brain APCs including microglia are only differential and positional polymorphs. Ann. Neurosci. 2010;17:191–199.
- Gonzalez R., Garitaonandia I., Crain A., Poustovoitov M., Abramihina T., Noskov A., Jiang C., Morey R., Laurent L.C., Elsworth J.D. Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson's disease. Cell Transplant. 2015;24:681–690.
- Gonzalez R., Garitaonandia I., Poustovoitov M., Abramihina T., McEntire C., Culp B., Attwood J., Noskov A., Christiansen-Weber T., Khater M. Neural stem cells derived from human parthenogenetic stem cells engraft and promote recovery in a nonhuman primate model of Parkinsons disease. Cell Transplant. 2016;25:1945–1966.
- Grealish S., Diguet E., Kirkeby A., Mattsson B., Heuer A., Bramoulle Y., Van Camp N., Perrier A.L., Hantraye P., Bjorklund A. 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;15:653–665.
- Gu Q., Wang J., Wang L., Liu Z.X., Zhu W.W., Tan Y.Q., Han W.F., Wu J., Feng C.J., Fang J.H. Accreditation of biosafe clinical-grade human embryonic stem cells according to Chinese regulations. Stem Cell Rep. 2017;9:366–380.
- Hallett P.J., Deleidi M., Astradsson A., Smith G.A., Cooper O., Osborn T.M., Sundberg M., Moore M.A., Perez-Torres E., Brownell A.L. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell. 2015;16:269–274.
- Hao J., Zhu W., Sheng C., Yu Y., Zhou Q. Human parthenogenetic embryonic stem cells: one potential resource for cell therapy. Sci. China C Life Sci. 2009;52:599–602.
- Hu B.Y., Weick J.P., Yu J., Ma L.X., Zhang X.Q., Thomson J.A., Zhang S.C. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA. 2010;107:4335–4340.
- Hyun I., Lindvall O., Ahrlund-Richter L., Cattaneo E., Cavazzana-Calvo M., Cossu G., De Luca M., Fox I.J., Gerstle C., Goldstein R.A. New ISSCR Guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell. 2008;3:607–609.
- Kettenmann H. Triggering the brain's pathology sensor. Nat. Neurosci. 2006;9:1463–1464.
- Kikuchi T., Morizane A., Doi D., Magotani H., Onoe H., Hayashi T., Mizuma H., Takara S., Takahashi R., Inoue H. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature. 2017;548:592–596.
- Kim S.H., Lee W.J., Lim H.K., Park C.K. SPIO-enhanced MRI findings of well-differentiated hepatocellular carcinomas: correlation with MDCT findings. Korean J. Radiol. 2009;10:112–120.
- Kriks S., Shim J.W., Piao J., Ganat Y.M., Wakeman D.R., Xie Z., Carrillo-Reid L., Auyeung G., Antonacci C., Buch A. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 2011;480:547–551.
- Lindvall O., Brundin P., Widner H., Rehncrona S., Gustavii B., Frackowiak R., Leenders K.L., Sawle G., Rothwell J.C., Marsden C.D. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science. 1990;247:574–577.
- Liu Y., Weick J.P., Liu H.S., Krencik R., Zhang X.Q., Ma L.X., Zhou G.M., Ayala M., Zhang S.C. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat. Biotechnol. 2013;31:440–447.
- Luan L., Ding F., Ai Y., Andersen A., Hardy P., Forman E., Gerhardt G.A., Gash D.M., Grondin R., Zhang Z. Pharmacological MRI (phMRI) monitoring of treatment in hemiparkinsonian rhesus monkeys. Cell Transplant. 2008;17:417–425.
- Ma L., Hu B., Liu Y., Vermilyea S.C., Liu H., Gao L., Sun Y., Zhang X., Zhang S.C. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell. 2012;10:455–464.
- Ma L., Liu Y., Zhang S.C. Directed differentiation of dopamine neurons from human pluripotent stem cells. Methods Mol. Biol. 2011;767:411–418.
- Ma L.X., Hu B.Y., Liu Y., Vermilyea S.C., Liu H.S., Gao L., Sun Y., Zhang X.Q., Zhang S.C. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell. 2012;10:455–464.
- Mai Q.Y., Yu Y., Li T., Wang L., Chen M.J., Huang S.Z., Zhou C.Q., Zhou Q. Derivation of human embryonic stem cell lines from parthenogenetic blastocysts. Cell Res. 2007;17:1008–1019.
- Morizane A., Darsalia V., Guloglu M.O., Hjalt T., Carta M., Li J.Y., Brundin P. A simple method for large-scale generation of dopamine neurons from human embryonic stem cells. J. Neurosci. Res. 2010;88:3467–3478.
- Morizane A., Doi D., Kikuchi T., Okita K., Hotta A., Kawasaki T., Hayashi T., Onoe H., Shiina T., Yamanaka S. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Rep. 2013;1:283–292.
- Olanow C.W., Goetz C.G., Kordower J.H., Stoessl A.J., Sossi V., Brin M.F., Shannon K.M., Nauert G.M., Perl D.P., Godbold J. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann. Neurol. 2003;54:403–414.
- Ovadia A., Zhang Z., Gash D.M. Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys. Neurobiol. Aging. 1995;16:931–937.
- Pankratz M.T., Li X.J., LaVaute T.M., Lyons E.A., Chen X., Zhang S.C. Directed neural differentiation of human embryonic stem cells via an obligated primitive anterior stage. Stem Cells. 2007;25:1511–1520.
- Ramos-Moreno T., Castillo C.G., Martinez-Serrano A. Long term behavioral effects of functional dopaminergic neurons generated from human neural stem cells in the rat 6-OH-DA Parkinson's disease model. Effects of the forced expression of BCL-X(L) Behav. Brain Res. 2012;232:225–232.
- Roggendorf W., Strupp S., Paulus W. Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol. 1996;92:288–293.
- Sanchez-Pernaute R., Studer L., Ferrari D., Perrier A., Lee H., Vinuela A., Isacson O. Long-term survival of dopamine neurons derived from parthenogenetic primate embryonic stem cells (Cyno-1) after transplantation. Stem Cells. 2005;23:914–922.
- Studer L., Psylla M., Buhler B., Evtouchenko L., Vouga C.M., Leenders K.L., Seiler R.W., Spenger C. Noninvasive dopamine determination by reversed phase HPLC in the medium of free-floating roller tube cultures of rat fetal ventral mesencephalon: a tool to assess dopaminergic tissue prior to grafting. Brain Res. Bull. 1996;41:143–150.
- Turovets N., Semechkin A., Kuzmichev L., Janus J., Agapova L., Revazova E. Derivation of human parthenogenetic stem cell lines. Methods Mol. Biol. 2011;767:37–54.
- Vogel D.Y., Vereyken E.J., Glim J.E., Heijnen P.D., Moeton M., van der Valk P., Amor S., Teunissen C.E., van Horssen J., Dijkstra C.D. Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J. Neuroinflammation. 2013;10:35.
- Wilkerson A., Wongsatittham K., Johnston J. The NIH stem cell registry: an absence of gamete donor consent. Cell Stem Cell. 2013;12:147–148.
- Xi J.J., Liu Y., Liu H.S., Chen H., Emborg M.E., Zhang S.C. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells. 2012;30:1655–1663.
- Yoo J., Kim H.S., Hwang D.Y. Stem cells as promising therapeutic options for neurological disorders. J. Cell Biochem. 2013;114:743–753.
Source: PubMed