Clonal Human (hNT) Neuron Grafts for Stroke Therapy: Neuropathology in a Patient 27 Months After Implantation

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2002 Apr 12

PMID 11943704

Citations 57

Authors

Peter T Nelson

Douglas Kondziolka

Lawrence Wechsler

Steven Goldstein

James Gebel

Sharon Decesare

Elaine M Elder

Paul J Zhang

Alan Jacobs

Michael McGrogan

Virginia M-Y Lee

John Q Trojanowski

Affiliations

Soon will be listed here.

Abstract

Although grafted cells may be promising therapy for stroke, survival of implanted neural cells in the brains of stroke patients has never been documented. Human NT2N (hNT) neurons derived from the NTera2 (NT2) teratocarcinoma cell line were shown to remain postmitotic, retain a neuronal phenotype, survive >1 year in host rodent brains and ameliorate motor and cognitive impairments in animal models of ischemic stroke. Here we report the first postmortem brain findings of a phase I clinical stroke trial patient implanted with human hNT neurons adjacent to a lacunar infarct 27 months after surgery. Neurofilament immunoreactive neurons were identified in the graft site, fluorescent in situ hybridization revealed polyploidy in groups of cells at this site just like polyploid hNT neurons in vitro, and there was no evidence of a neoplasm. These findings indicate that implanted hNT neurons survive for >2 years in the human brain without deleterious effects.

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References

Zigova T, Barroso L, Willing A, Saporta S, McGrogan M, Freeman T . Dopaminergic phenotype of hNT cells in vitro. Brain Res Dev Brain Res. 2000; 122(1):87-90. DOI: 10.1016/s0165-3806(00)00055-9. View

Fink J, Schumacher J, Ellias S, PALMER E, Saint-Hilaire M, Shannon K . Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant. 2000; 9(2):273-8. DOI: 10.1177/096368970000900212. View

Lee V, Hartley R, Trojanowski J . Neurobiology of human neurons (NT2N) grafted into mouse spinal cord: implications for improving therapy of spinal cord injury. Prog Brain Res. 2000; 128:299-307. DOI: 10.1016/S0079-6123(00)28027-8. View

Freeman T, Cicchetti F, Hauser R, Deacon T, Li X, Hersch S . Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc Natl Acad Sci U S A. 2000; 97(25):13877-82. PMC: 17669. DOI: 10.1073/pnas.97.25.13877. View

Saporta S, Willing A, Colina L, Zigova T, Milliken M, Daadi M . In vitro and in vivo characterization of hNT neuron neurotransmitter phenotypes. Brain Res Bull. 2000; 53(3):263-8. DOI: 10.1016/s0361-9230(00)00329-4. View

Yang Y, Geldmacher D, Herrup K . DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001; 21(8):2661-8. PMC: 6762514. View

Meltzer C, Kondziolka D, Villemagne V, Wechsler L, Goldstein S, Thulborn K . Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery. 2001; 49(3):586-91; discussion 591-2. DOI: 10.1097/00006123-200109000-00011. View

Borlongan C, Tajima Y, Trojanowski J, Lee V, Sanberg P . Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol. 1998; 149(2):310-21. DOI: 10.1006/exnr.1997.6730. View

Andrews P . Teratocarcinomas and human embryology: pluripotent human EC cell lines. Review article. APMIS. 1998; 106(1):158-67; discussion 167-8. DOI: 10.1111/j.1699-0463.1998.tb01331.x. View

10.

Borlongan C, Saporta S, Poulos S, Othberg A, Sanberg P . Viability and survival of hNT neurons determine degree of functional recovery in grafted ischemic rats. Neuroreport. 1998; 9(12):2837-42. DOI: 10.1097/00001756-199808240-00028. View

11.

Andrews P . Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev Biol. 1984; 103(2):285-93. DOI: 10.1016/0012-1606(84)90316-6. View

12.

Wolf P, Kannel W, Verter J . Current status of risk factors for stroke. Neurol Clin. 1983; 1(1):317-43. View

13.

Kojima S, Omura T, Wakamatsu W, Kishi M, Yamazaki T, Iida M . Prognosis and disability of stroke patients after 5 years in Akita, Japan. Stroke. 1990; 21(1):72-7. DOI: 10.1161/01.str.21.1.72. View

14.

Pleasure S, Page C, Lee V . Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J Neurosci. 1992; 12(5):1802-15. PMC: 6575890. View

15.

Trojanowski J, Mantione J, Lee J, Seid D, You T, Inge L . Neurons derived from a human teratocarcinoma cell line establish molecular and structural polarity following transplantation into the rodent brain. Exp Neurol. 1993; 122(2):283-94. DOI: 10.1006/exnr.1993.1128. View

16.

Netto C, Hodges H, Sinden J, LePeillet E, Kershaw T, Sowinski P . Foetal grafts from hippocampal regio superior alleviate ischaemic-induced behavioural deficits. Behav Brain Res. 1993; 58(1-2):107-12. DOI: 10.1016/0166-4328(93)90095-8. View

17.

Miyazono M, Lee V, Trojanowski J . Proliferation, cell death, and neuronal differentiation in transplanted human embryonal carcinoma (NTera2) cells depend on the graft site in nude and severe combined immunodeficient mice. Lab Invest. 1995; 73(2):273-83. View

18.

Grabowski M, Johansson B, Brundin P . Fetal neocortical grafts placed in brain infarcts do not improve paw-reaching deficits in adult spontaneously hypertensive rats. Acta Neurochir Suppl. 1996; 66:68-72. DOI: 10.1007/978-3-7091-9465-2_12. View

19.

Miyazono M, Nowell P, Finan J, Lee V, Trojanowski J . Long-term integration and neuronal differentiation of human embryonal carcinoma cells (NTera-2) transplanted into the caudoputamen of nude mice. J Comp Neurol. 1996; 376(4):603-13. DOI: 10.1002/(SICI)1096-9861(19961223)376:4<603::AID-CNE8>3.0.CO;2-5. View

20.

Dunlop J, McIlvain H, Lou Z, Franco R . The pharmacological profile of L-glutamate transport in human NT2 neurones is consistent with excitatory amino acid transporter 2. Eur J Pharmacol. 1998; 360(2-3):249-56. DOI: 10.1016/s0014-2999(98)00675-x. View