Notch, Wnt and Shh neurogenic signaling co-regulation in reactive astrocyte response

• Autor(a) principal: Delgado-Garcia, Lina Maria [UNIFESP]
• Data de Publicação: 2022
• Tipo de documento: Tese
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: https://repositorio.unifesp.br/xmlui/handle/11600/63877
• topic: Biologia das células gliais; Vias de sinalização neurogênica; Traumatismo cranioencefálico; Glial biology; Neurogenic signaling pathways; Neuroprotection; Morphogens; Traumatic brain injury

After a TBI, the neural network activates a reparative response seeking to restore homeostasis in the affected area. Astrocyte reactivation is an essential component of this response. Understanding astroglial cell functional heterogeneity and dissecting the role of supportive molecules in brain damage is crucial for our current comprehension of the mechanisms leading to the repair and regeneration of the CNS and the development of novel therapeutic interventions. In this thesis, we study cellular and molecular aspects of reactive astrocytes and Notch, Wnt and Shh neurogenic signaling modulation response. We used an in vivo model of brain damage by TBI and an in vitro model of wound healing and astrocyte reactivation by scratch. We found Notch (NICD) and Wnt (active β-catenin) upregulation and described signaling concentration patterns in the cortex of mice submitted to TBI. Reactive astrocytes presented an aggregated distribution in the core of Notch signaling. We evaluated the functional heterogeneity and plasticity of the progeny of E14 mice -GFAP StarTrack in utero electroporated active neural progenitors. Lower layer protoplasmic astrocytes showed a strong reactive response. Upper and lower layers protoplasmic reactive astrocytes close to the lesion borders showed increased polarization and enrichment of mesh-like structures. In vitro treatment with LY450139 Semagacestat inhibited Notch - HEY signaling. Notch inhibition may attenuate reactive astrocytes response and activate neural precursor mechanisms. Finally, we suggest indirect co-regulation of Wnt-Shh signaling in BHLH-Notch target genes after Notch inhibition. Similarly, Notch inhibition may also have a supportive effect in Wnt-Shh signaling activation. Above all, this thesis contributes to increasing our knowledge of glia biology and the regenerative role of neurogenic signaling molecules in the response of reactive astrocytes after brain injury.