Expandable Sendai-Virus-Reprogrammed Human iPSC-Neuronal Precursors: In Vivo Post-Grafting Safety Characterization in Rats and Adult Pig
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
37088987
PubMed Central
PMC10134149
DOI
10.1177/09636897221107009
Knihovny.cz E-resources
- Keywords
- cryopreservation, human induced pluripotent stem cells (hiPSCs), human injection device, immunosuppressed adult pig, neural precursor cells (NPCs), spinal cord,
- MeSH
- Cell Differentiation physiology MeSH
- Adult MeSH
- Genetic Vectors genetics MeSH
- Induced Pluripotent Stem Cells * physiology transplantation MeSH
- Rats MeSH
- Humans MeSH
- Spinal Cord MeSH
- Brain MeSH
- Neural Stem Cells * physiology transplantation MeSH
- Specimen Handling methods MeSH
- Tissue and Organ Harvesting methods MeSH
- Swine MeSH
- Cellular Reprogramming * genetics physiology MeSH
- Graft Survival physiology MeSH
- Injections, Spinal * adverse effects instrumentation methods MeSH
- Stem Cell Transplantation * adverse effects instrumentation methods MeSH
- Sendai virus MeSH
- Treatment Outcome MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
One of the challenges in clinical translation of cell-replacement therapies is the definition of optimal cell generation and storage/recovery protocols which would permit a rapid preparation of cell-treatment products for patient administration. Besides, the availability of injection devices that are simple to use is critical for potential future dissemination of any spinally targeted cell-replacement therapy into general medical practice. Here, we compared the engraftment properties of established human-induced pluripotent stem cells (hiPSCs)-derived neural precursor cell (NPCs) line once cells were harvested fresh from the cell culture or previously frozen and then grafted into striata or spinal cord of the immunodeficient rat. A newly developed human spinal injection device equipped with a spinal cord pulsation-cancelation magnetic needle was also tested for its safety in an adult immunosuppressed pig. Previously frozen NPCs showed similar post-grafting survival and differentiation profile as was seen for freshly harvested cells. Testing of human injection device showed acceptable safety with no detectable surgical procedure or spinal NPCs injection-related side effects.
Department of Anesthesiology School of Medicine University of California San Diego San Diego CA USA
Department of Neurosurgery School of Medicine University of California San Diego San Diego CA USA
Department of Orthopedic Surgery Keio University School of Medicine Tokyo Japan
Institute of Animal Physiology and Genetics AS CR v v i Liběchov Czech Republic
Regenerative and Cellular Medicine Kobe Center Sumitomo Dainippon Pharma Co Ltd Kobe Japan
See more in PubMed
Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000;3(6):537–44. PubMed
Gage FH. Mammalian neural stem cells. Science. 2000;287(5457):1433–38. PubMed
Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;441(7097):1094–96. PubMed
Kakinohana O, Juhasova J, Juhas S, Motlik J, Platoshyn O, Galik J, Hefferan M, Yuan SH, Vidal JG, Carson CT, van Gorp S, et al.. Survival and differentiation of human embryonic stem cell-derived neural precursors grafted spinally in spinal ischemia-injured rats or in naive immunosuppressed minipigs: a qualitative and quantitative study. Cell Transplant. 2012;21(12):2603–19. PubMed
Cizkova D, Kakinohana O, Kucharova K, Marsala S, Johe K, Hazel T, Hefferan MP, Marsala M. Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells. Neuroscience. 2007;147(2):546–60. PubMed PMC
Marsala M, Kakinohana O, Yaksh TL, Tomori Z, Marsala S, Cizkova D. Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. Eur J Neurosci. 2004;20(9):2401–14. PubMed
van Gorp S, Leerink M, Kakinohana O, Platoshyn O, Santucci C, Galik J, Joosten EA, Hruska-Plochan M, Goldberg D, Marsala S, Johe K, et al.. Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation. Stem Cell Res Ther. 2013;4(3):57. PubMed PMC
Tarasenko YI, Gao J, Nie L, Johnson KM, Grady JJ, Hulsebosch CE, McAdoo DJ, Wu P. Human fetal neural stem cells grafted into contusion-injured rat spinal cords improve behavior. J Neurosci Res. 2007;85(1):47–57. PubMed
Kumagai G, Okada Y, Yamane J, Nagoshi N, Kitamura K, Mukaino M, Tsuji O, Fujiyoshi K, Katoh H, Okada S, Shibata S, et al.. Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury. PLoS ONE. 2009;4(11):e7706. PubMed PMC
Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y, Okano H. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res. 2002;69(6):925–33. PubMed
Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS ONE. 2010;5(8):e12272. PubMed PMC
Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8(3):346–53. PubMed
Iwanami A, Kaneko S, Nakamura M, Kanemura Y, Mori H, Kobayashi S, Yamasaki M, Momoshima S, Ishii H, Ando K, Tanioka Y, et al.. Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res. 2005;80(2):182–90. PubMed
Mitsui T, Shumsky JS, Lepore AC, Murray M, Fischer I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J Neurosci. 2005;25(42):9624–36. PubMed PMC
Bonner JF, Connors TM, Silverman WF, Kowalski DP, Lemay MA, Fischer I. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci. 2011;31(12):4675–86. PubMed PMC
Wilcox JT, Satkunendrarajah K, Zuccato JA, Nassiri F, Fehlings MG. Neural precursor cell transplantation enhances functional recovery and reduces astrogliosis in bilateral compressive/contusive cervical spinal cord injury. Stem Cells Transl Med. 2014;3(10):1148–59. PubMed PMC
Suzuki H, Ahuja CS, Salewski RP, Li L, Satkunendrarajah K, Nagoshi N, Shibata S, Fehlings MG. Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. PLoS ONE. 2017;12(8):e0182339. PubMed PMC
Nagoshi N, Khazaei M, Ahlfors JE, Ahuja CS, Nori S, Wang J, Shibata S, Fehlings MG. Human spinal oligodendrogenic neural progenitor cells promote functional recovery after spinal cord injury by axonal remyelination and tissue sparing. Stem Cells Transl Med. 2018;7(11):806–18. PubMed PMC
Rosenzweig ES, Brock JH, Lu P, Kumamaru H, Salegio EA, Kadoya K, Weber JL, Liang JJ, Moseanko R, Hawbecker S, Huie JR, et al.. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med. 2018;24(4):484–90. PubMed PMC
Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, Boehle E, Ahmad R, Poplawski G, Brock J, Goldstein LSB, et al.. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron. 2014;83(4):789–96. PubMed PMC
Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Kumamaru H, Yao L, Knackert J, Poplawski G, Dulin JN, Strobl H, Takashima Y, et al.. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 2016;22(5):479–87. PubMed PMC
Hefferan MP, Galik J, Kakinohana O, Sekerkova G, Santucci C, Marsala S, Navarro R, Hruska-Plochan M, Johe K, Feldman E, Cleveland DW, et al.. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS ONE. 2012;7(8):e42614. PubMed PMC
Zalfa C, Rota Nodari L, Vacchi E, Gelati M, Profico D, Boido M, Binda E, De Filippis L, Copetti M, Garlatti V, Daniele P, et al.. Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats. Cell Death Dis. 2019; 10(5):345. PubMed PMC
Bohaciakova D, Hruska-Plochan M, Tsunemoto R, Gifford WD, Driscoll SP, Glenn TD, Wu S, Marsala S, Navarro M, Tadokoro T, Juhas S, et al.. A scalable solution for isolating human multipotent clinical-grade neural stem cells from ES precursors. Stem Cell Res Ther. 2019;10(1):83. PubMed PMC
Nishimura S, Yasuda A, Iwai H, Takano M, Kobayashi Y, Nori S, Tsuji O, Fujiyoshi K, Ebise H, Toyama Y, Okano H, et al.. Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury. Mol Brain. 2013;6:3. PubMed PMC
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. PubMed
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. PubMed
Cheng C, Fass DM, Folz-Donahue K, MacDonald ME, Haggarty SJ. Highly expandable human iPS cell-derived neural progenitor cells (NPC) and neurons for central nervous system disease modeling and high-throughput screening. Curr Protoc Hum Genet. 2017;92:21.8.1–21. PubMed PMC
Tcw J, Wang M, Pimenova AA, Bowles KR, Hartley BJ, Lacin E, Machlovi SI, Abdelaal R, Karch CM, Phatnani H, Slesinger PA, et al.. An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Rep. 2017;9(2):600–14. PubMed PMC
Gorris R, Fischer J, Erwes KL, Kesavan J, Peterson DA, Alexander M, Nothen MM, Peitz M, Quandel T, Karus M, Brüstle O. Pluripotent stem cell-derived radial glia-like cells as stable intermediate for efficient generation of human oligodendrocytes. Glia. 2015;63(12):2152–67. PubMed
Kawabata S, Takano M, Numasawa-Kuroiwa Y, Itakura G, Kobayashi Y, Nishiyama Y, Sugai K, Nishimura S, Iwai H, Isoda M, Shibata S, et al.. Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury. Stem Cell Rep. 2016;6(1):1–8. PubMed PMC
Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, Sekiguchi K, Nakagawa M, Parmar M, Takahashi J. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Rep. 2014;2(3):337–50. PubMed PMC
Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, Fujiyoshi K, Koike M, Uchiyama Y, Ikeda E, Toyama Y, et al.. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci U S A. 2011;108(40):16825–30. PubMed PMC
Kobayashi Y, Okada Y, Itakura G, Iwai H, Nishimura S, Yasuda A, Nori S, Hikishima K, Konomi T, Fujiyoshi K, Tsuji O, Toyama Y, et al.. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS ONE. 2012;7(12):e52787. PubMed PMC
Kondo T, Funayama M, Tsukita K, Hotta A, Yasuda A, Nori S, Kaneko S, Nakamura M, Takahashi R, Okano H, Yamanaka S, et al.. Focal transplantation of human iPSC-derived glial-rich neural progenitors improves lifespan of ALS mice. Stem Cell Rep. 2014;3(2):242–49. PubMed PMC
Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, Mizuma H, Takara S, Takahashi R, Inoue H, Morita S, et al.. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature. 2017;548(7669): 592–96. PubMed
Curtis E, Martin JR, Gabel B, Sidhu N, Rzesiewicz TK, Mandeville R, Van Gorp S, Leerink M, Tadokoro T, Marsala S, Ciacci JD. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell. 2018;22(6):941–50.e6. PubMed
Levi AD, Okonkwo DO, Park P, Jenkins AL, III, Kurpad SN, Parr AM, Ganju A, Aarabi B, Kim D, Casha S, Fehlings MG, et al.. Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery. 2018;82(4):562–75. PubMed
Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, Muzi G, Ricciolini C, Rota Nodari L, Carletti S, Giorgi C, Spera C, et al.. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015;13:17. PubMed PMC
Riley J, Federici T, Polak M, Kelly C, Glass J, Raore B, Taub J, Kesner V, Feldman EL, Boulis NM. Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes. Neurosurgery. 2012;71(2):405–16; discussion 416. PubMed
Madrazo I, Kopyov O, Avila-Rodriguez MA, Ostrosky F, Carrasco H, Kopyov A, Avendano-Estrada A, Jimenez F, Magallon E, Zamorano C, González G, et al.. Transplantation of human neural progenitor cells (NPC) into putamina of Parkinsonian patients: a case series study, safety and efficacy four years after surgery. Cell Transplant. 2019;28(3):269–85. PubMed PMC
Lige L, Zengmin T. Transplantation of neural precursor cells in the treatment of Parkinson disease: an efficacy and safety analysis. Turk Neurosurg. 2016;26(3):378–83. PubMed
Usvald D, Vodicka P, Hlucilova J, Prochazka R, Motlik J, Kuchorova K, Johe K, Marsala S, Scadeng M, Kakinohana O, Navarro R, Santa M, et al.. Analysis of dosing regimen and reproducibility of intraspinal grafting of human spinal stem cells in immunosuppressed minipigs. Cell Transplant. 2010;19(9):1103–22. PubMed
Sevc J, Goldberg D, van Gorp S, Leerink M, Juhas S, Juhasova J, Marsala S, Hruska-Plochan M, Hefferan MP, Motlik J, Rypacek F, et al.. Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: effect on spinally grafted human neural precursor survival. Exp Neurol. 2013;248:85–99. PubMed
Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12(1):1–21. PubMed
Navarro R, Juhas S, Keshavarzi S, Juhasova J, Motlik J, Johe K, Marsala S, Scadeng M, Lazar P, Tomori Z, Schulteis G, et al.. Chronic spinal compression model in minipigs: a systematic behavioral, qualitative, and quantitative neuropathological study. J Neurotrauma. 2012;29(3):499–513. PubMed PMC
Marsala M, Kamizato K, Tadokoro T, Navarro M, Juhas S, Juhasova J, Marsala S, Studenovska H, Proks V, Hazel T, Johe K, et al.. Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats. Stem Cells Transl Med. 2020;9(2):177–88. PubMed PMC
Glass JD, Hertzberg VS, Boulis NM, Riley J, Federici T, Polak M, Bordeau J, Fournier C, Johe K, Hazel T, Cudkowicz M, et al.. Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology. 2016;87(4):392–400. PubMed PMC
Strnadel J, Carromeu C, Bardy C, Navarro M, Platoshyn O, Glud AN, Marsala S, Kafka J, Miyanohara A, Kato T, Jr, Tadokoro T, et al.. Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs. Sci Transl Med. 2018;10(440):eaam6651. PubMed
Rosati J, Ferrari D, Altieri F, Tardivo S, Ricciolini C, Fusilli C, Zalfa C, Profico DC, Pinos F, Bernardini L, Torres B, et al.. Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies. Cell Death Dis. 2018;9(10):937. PubMed PMC
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, et al.. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264–73. PubMed PMC
Koffler J, Zhu W, Qu X, Platoshyn O, Dulin JN, Brock J, Graham L, Lu P, Sakamoto J, Marsala M, Chen S, et al.. Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat Med. 2019;25(2):263–69. PubMed PMC
Andsberg G, Kokaia Z, Björklund A, Lindvall O, Martínez-Serrano A. Amelioration of ischaemia-induced neuronal death in the rat striatum by NGF-secreting neural stem cells. Eur J Neurosci. 1998;10(6):2026–36. PubMed
Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, Logvinova A, Banwait S, Greenberg DA. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis. 2005;18(2):366–74. PubMed
Buhnemann C, Scholz A, Bernreuther C, Malik CY, Braun H, Schachner M, Reymann KG, Dihne M. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain. 2006;129(pt 12):3238–48. PubMed
Jin K, Xie L, Mao X, Greenberg MB, Moore A, Peng B, Greenberg RB, Greenberg DA. Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Res. 2011;1374:56–62. PubMed PMC
Memanishvili T, Kupatadze N, Tugushi D, Katsarava R, Wattananit S, Hara N, Tornero D, Kokaia Z. Generation of cortical neurons from human induced-pluripotent stem cells by biodegradable polymeric microspheres loaded with priming factors. Biomed Mater. 2016;11(2):025011. PubMed
Jirak D, Ziolkowska N, Turnovcova K, Karova K, Sykova E, Jendelova P, Romanyuk N. Metabolic changes in focal brain ischemia in rats treated with human induced pluripotent stem cell-derived neural precursors confirm the beneficial effect of transplanted cells. Front Neurol. 2019;10:1074. PubMed PMC
Skop NB, Calderon F, Cho CH, Gandhi CD, Levison SW. Optimizing a multifunctional microsphere scaffold to improve neural precursor cell transplantation for traumatic brain injury repair. J Tissue Eng Regen Med. 2016;10(10):E419–32. PubMed
Maisano X, Carpentino J, Becker S, Lanza R, Aaron G, Grabel L, Naegele JR. Embryonic stem cell-derived neural precursor grafts for treatment of temporal lobe epilepsy. Neurotherapeutics. 2009;6(2):263–77. PubMed PMC
Makri G, Lavdas AA, Katsimpardi L, Charneau P, Thomaidou D, Matsas R. Transplantation of embryonic neural stem/precursor cells overexpressing BM88/Cend1 enhances the generation of neuronal cells in the injured mouse cortex. Stem Cells. 2010;28(1):127–39. PubMed
Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci. 2008;11(11):1294–301. PubMed PMC
Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, Geraghty T, Mackay-Sim A. Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain. 2005; 128(pt 12):2951–60. PubMed
Anderson KD, Guest JD, Dietrich WD, Bartlett Bunge M, Curiel R, Dididze M, Green BA, Khan A, Pearse DD, Saraf-Lavi E, Widerström-Noga E, et al.. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma. 2017;34(21):2950–63. PubMed