Human neural stem cell transplants improve motor function in a rat model of Huntington's disease

The present study investigated the neuroanatomical and behavioral effects of human stem cell transplants into the striatum of quinolinic acid (QA)‐lesioned rats. Twenty‐four rats received unilateral QA (200 nM/μl) injections into the striatum. One week later, rats were transplanted with stem cells derived from human fetal cortex (12 weeks postconception) that were either 1) pretreated in culture media with the differentiating cytokine ciliary neurotrophic factor (CNTF; n = 9) or 2) allowed to grow in culture media alone (n = 7). Each rat was injected with a total of 200,000 cells. A third group of rats (n = 8) was given a sham injection of vehicle. Rats transplanted with human stem cells performed significantly better over the 8 weeks of testing on the cylinder test compared with those treated with vehicle (P ≤ 0.001). Stereological striatal volume analyses performed on Nissl‐stained sections revealed that rats transplanted with CNTF‐treated neurospheres had a 22% greater striatal volume on the lesioned side compared with those receiving transplants of untreated neurospheres (P = 0.0003) and a 26% greater striatal volume compared with rats injected with vehicle (P ≤ 0.0001). Numerous human nuclei‐positive cells were visualized in the striatum in both transplantation groups. Grafted cells were also observed in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata, areas of the basal ganglia receiving striatal projections. Some of the human nuclei‐positive cells coexpressed glial fibrillary acidic protein and NeuN, suggesting that they had differentiated into neurons and astrocytes. Taken together, these data demonstrate that striatal transplants of human fetal stem cells elicit behavioral and anatomical recovery in a rodent model of Huntington's disease. J. Comp. Neurol. 475:211–219, 2004. © 2004 Wiley‐Liss, Inc.

[1]  Clive N Svendsen,et al.  A new method for the rapid and long term growth of human neural precursor cells , 1998, Journal of Neuroscience Methods.

[2]  D. Reis,et al.  Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist. , 1987, Science.

[3]  Scott Pollack,et al.  Growth factors regulate the survival and fate of cells derived from human neurospheres , 2001, Nature Biotechnology.

[4]  M. Tuszynski,et al.  Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury , 2003, Experimental Neurology.

[5]  Françoise Condé,et al.  Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease , 1998, Nature Medicine.

[6]  T. Deacon,et al.  Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Gluckman,et al.  Neuroprotective strategies for basal ganglia degeneration: Parkinson’s and Huntington’s diseases , 2000, Progress in Neurobiology.

[8]  C. Svendsen,et al.  Neural stem cells in the developing central nervous system: implications for cell therapy through transplantation. , 2000, Progress in brain research.

[9]  Melitta Schachner,et al.  Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons , 2002, Nature Biotechnology.

[10]  A. Björklund,et al.  The integration and function of striatal grafts. , 2000, Progress in brain research.

[11]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[12]  Julie S. Snowden,et al.  Neuropsychological and neuropsychiatric aspects of Huntington's disease , 2002 .

[13]  A. Björklund,et al.  Striatal grafts in rats with unilateral neostriatal lesions—III. Recovery from dopamine-dependent motor asymmetry and deficits in skilled paw reaching , 1988, Neuroscience.

[14]  E. Jauniaux,et al.  Regional specification of rodent and human neurospheres. , 2002, Brain research. Developmental brain research.

[15]  S. Weiss,et al.  Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. , 1996, Developmental biology.

[16]  C. Svendsen,et al.  Recent advances in stem cell neurobiology. , 2003, Advances and technical standards in neurosurgery.

[17]  Monte A. Gates,et al.  Site-Specific Migration and Neuronal Differentiation of Human Neural Progenitor Cells after Transplantation in the Adult Rat Brain , 1999, The Journal of Neuroscience.

[18]  A. Björklund,et al.  Migration patterns and phenotypic differentiation of long-term expanded human neural progenitor cells after transplantation into the adult rat brain. , 2002, Brain research. Developmental brain research.

[19]  R. Barker,et al.  Neural cells from primary human striatal xenografts migrate extensively in the adult rat CNS , 2002, The European journal of neuroscience.