Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

Abstract

ObjectiveTransplanting 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.MethodsHuman 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.ResultsAlthough 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.InterpretationThe 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.

Meninges harbor cells expressing neural precursor markers during development and adulthood

“…Previous works described the presence in adult meninges of a stem cell-like population that reacts to CNS injury by displaying the hallmarks of a neural stem cell niche: activation, increased proliferation and migration to the lesioned parenchyma (Decimo et al, 2011 ; Nakagomi et al, 2011 , 2012 ; Ninomiya et al, 2013 ; Kumar et al, 2014 ). Moreover, a population of nestin-positive cells could be extracted from meningeal tissue, cultured in vitro and showed neural differentiation potential in vitro and after transplantation in vivo (Bifari et al, 2009 ; Nakagomi et al, 2011 ).…”

“…Cells isolated from both brain and spinal cord leptomeninges could be differentiated into neurons and oligodendrocytes in vitro ; after transplantation in vivo these cells integrate in hippocampal CA1 region acquiring neuronal morphology (Bifari et al, 2009 ). Of note, following injury meningeal cells increase their proliferation rate, migrate into the parenchyma, contribute to the injury-induced reaction (Decimo et al, 2011 ; Kumar et al, 2014 ) and increase their expression of neural progenitor markers (Decimo et al, 2011 ; Nakagomi et al, 2011 , 2012 ; Ninomiya et al, 2013 ).…”

Effect of fetal cerebellar tissue transplantation on the restoration of hind limb locomotor function in rats with spinal cord injury

“…Between 15-28 weeks of prenatal development in human the surface area of the cerebellar cortex increases by 30 times [28]. These neurometric data, a number of other facts [29][30][31][32][33], as well as data on the role of postnatal neurogenic progenitors' population of the cerebellum in children medulloblastoma formation [34][35][36] indicate the high potential of cerebellar neurogenic population at the time of birth. Rat cerebellar tissue obtained in late gestation (E18) or immediately after the birth contains perhaps the largest number of neurogenic progenitors committed to differentiation into glutamatergic neurons (granule cells).…”

Solving the Neurogenesis Puzzle: Looking for Pieces Outside the Traditional Box

“…Cells are born and migrate from and within the cerebellum, with roughly half possessing a neuronal phenotype and integrating into existing networks of cerebellar neurons. By contrast, the cerebellum has long been considered the most static region within the adult mammalian brain (Altman, 1969 ), with researchers rejecting the prospect of constitutive cerebellar neurogenesis despite some evidence of cell proliferation (albeit glial phenotypes) in the cerebellum of mice and rats (Grimaldi and Rossi, 2006 ; Su et al, 2014 ) and manipulation-induced generation of neurons in the cerebellum of cats and mice (Tighilet et al, 2007 ; Kumar et al, 2014 ). Yet, evidence supports the presence of constitutively active neuronal and glial progenitors in the cerebellar cortex of peripubertal and adult rabbits ( Orictolagus cuniculus ), perhaps owing to the longevity of rabbits as compared to other mammalian species studied (Ponti et al, 2006 , 2008 ).…”