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Endogenous cerebellar neurogenesis in adult mice with progressive ataxia
Author(s) -
Kumar Manoj,
Csaba Zsolt,
Peineau Stéphane,
Srivastava Rupali,
Rasika Sowmyalakshmi,
Mani Shyamala,
Gressens Pierre,
El Ghouzzi Vincent
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.137
Subject(s) - neurogenesis , neuroscience , cerebellum , progenitor cell , transplantation , granule cell , biology , population , medicine , pathology , stem cell , microbiology and biotechnology , central nervous system , dentate gyrus , environmental health
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 GNP s 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 GNP s. 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 GNP s not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.

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