Wnt, SHH and Notch signalling crosstalk in the acquisition of stem cell phenotype by reactive astrocytes

Abstract

Specialized regions within the central nervous system (CNS), known as neurogenic niches, recapitulate the generation of neural cells occurring during development. In this process, neural stem cells originate glia and neurons. Two regions in the CNS are well characterized as neurogenic niches in the adult brain: the subventricular zone (SVZ) of the lateral ventricles and the hippocampal subgranular zone. Although new neurons are produced at the neurogenic niches of adult brains, the ability of those cells to participate in the regenerative process of the nervous tissue is very limited. The low regenerative potential of the CNS has consequences, sometimes very serious, to those individuals whose brain is affected by traumatic injuries, stroke or neurodegenerative disorders. For the last 10 years our lab has been studying the cellular and molecular mechanisms of neural stem cell response to traumatic brain injury (TBI) aiming to propose possible new therapeutic strategies to treat those injuries. In that period we obtained interesting results that, together with data from the literature, increased our knowledge of cellular and molecular mechanisms involved in the control of neural stem cell response to a cortical TBI model in mice. Using animal models for TBI and stroke we tested therapeutic strategies such as chondroitin sulfate degradation to decrease inhibition of migration and axonal outgrowth at the lesion site; mesenchimal stem cell transplantation at the injury site to modulate the local inflammatory response; and administration of CXCL12 fragments at the injury site to increase neuroblasts chemoattraction. Nevertheless, until now, no strategy has proven successful to diminish functional losses by mice submitted to the lesion models. In this scenario, we search for a new hypothesis to try to understand and, eventually, revert the lack of CNS regeneration. Data from the literature have shown that neuronal characteristics are determined by intrinsic mechanisms established before differentiation in mature neurons. During development, exposition of the neuroepithelial cells to morphogenic factors establishes distinct territories of transcription factors expression. Although stem cells present at the neurogenic niche in the adult SVZ increase proliferation in response to injury-associated stimuli, newborn neurons are not capable to produce full tissue regeneration. Similar to what happens to neural stem cells, glial cells are also affected by the injury, particularly, the astrocytes that are activated by soluble factors released at the injury. Activated astrocytes, also know as reactive astrocytes, are clearly different from non-activated astrocytes. Among the alterations are changes in gene expression, enhanced proliferation and dedifferentiation. Recently, data from the literature have shown that a small part of reactive astrocytes acquire neural stem cell phenotype as product of the activation and dedifferentiation process. The working hypothesis of this project is that, in vivo, reactive astrocytes could be an alternative source of neural stem cells in the adult brain. (AU)