Neuroprotection of Host Cells by Human Central Nervous System Stem Cells in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis

Stanley J. Tamaki, Yakop Jacobs, Monika Dohse, Alexandra Capela, Jonathan D. Cooper, Michael Reitsma, Dongping He, Robert Tushinski, Pavel V. Belichenko, Ahmad Salehi, William Mobley, Fred H. Gage, Stephen Huhn, Ann S. Tsukamoto, Irving L. Weissman, Nobuko Uchida

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disease caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Ppt1 knockout mice display hallmarks of INCL and mimic the human pathology: accumulation of lipofuscin, degeneration of CNS neurons, and a shortened life span. Purified non-genetically modified human CNS stem cells, grown as neurospheres (hCNS-SCns), were transplanted into the brains of immunodeficient Ppt1-/- mice where they engrafted robustly, migrated extensively, and produced sufficient levels of PPT1 to alter host neuropathology. Grafted mice displayed reduced autofluorescent lipofuscin, significant neuroprotection of host hippocampal and cortical neurons, and delayed loss of motor coordination. Early intervention with cellular transplants of hCNS-SCns into the brains of INCL patients may supply a continuous and long-lasting source of the missing PPT1 and provide some therapeutic benefit through protection of endogenous neurons. These data provide the experimental basis for human clinical trials with these banked hCNS-SCns.

Original languageEnglish
Pages (from-to)310-319
Number of pages10
JournalCell Stem Cell
Volume5
Issue number3
DOIs
StatePublished - Sep 4 2009
Externally publishedYes

Keywords

  • HUMDISEASE
  • STEMCELL

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    Tamaki, S. J., Jacobs, Y., Dohse, M., Capela, A., Cooper, J. D., Reitsma, M., He, D., Tushinski, R., Belichenko, P. V., Salehi, A., Mobley, W., Gage, F. H., Huhn, S., Tsukamoto, A. S., Weissman, I. L., & Uchida, N. (2009). Neuroprotection of Host Cells by Human Central Nervous System Stem Cells in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis. Cell Stem Cell, 5(3), 310-319. https://doi.org/10.1016/j.stem.2009.05.022