Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

Manoj Kumar, Zsolt Csaba, Stéphane Peineau, Rupali Srivastava, Sowmyalakshmi Rasika, Shyamala Mani, Pierre Gressens, Vincent El Ghouzzi

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis. Methods: Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis. Results: Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs. Interpretation: The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.

Original languageEnglish (US)
Pages (from-to)968-981
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume1
Issue number12
DOIs
StatePublished - Dec 2014
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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