Modeling the radial glia niche: Deciphering key mechanotransduction components

dc.contributor
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.contributor.author
Soriano Esqué, José Pablo
dc.date.accessioned
2024-07-22T09:10:54Z
dc.date.issued
2024-04-26
dc.identifier.uri
http://hdl.handle.net/10803/691845
dc.description
Programa de Doctorat en Biomedicina
ca
dc.description.abstract
[eng] Radial glial (RG) are the principal neural stem cells of the embryonic brain, giving rise to intermediate progenitors and fate-committed neural cell types, and serving as a mechanical scaffold for neuron migration and correct cortical patterning. The lack of RG cells in the adult brain is considered a hallmark of the reduced endogenous brain regenerative capacity in some species. From the mechanobiology point of view, brain histogenesis encompasses a continuum of mechanical cues, metabolic shifts and transcriptional changes that orchestrate the construction of a healthy brain through a fine-tuned balance of mechanotransducive processes. The use of biomaterial-based strategies provides an excellent opportunity to model the architectural features of the embryonic brain. Ln2PMMA is an RG biomimetic substrate of poly methyl methacrylate with 2μm linear topography that reproduced the surface properties and mechanical anisotropy of the RG niche during embryonic brain development, with the capability to induce cultured astrocytes to dedifferentiate into functional RG cells. Although the mechanotransducive components underlying this process are largely unknown. In this Doctoral Thesis, we used mouse cortical glial cultures and ln2PMMA RG biomimetic material as a robust biomechanical tool for the in vitro analysis of mechanotransducive mechanisms involved in RG linage differentiation, allowing us to define some of the mechano-electrical -metabolic and -nuclear components of the astrocyte-RG lineage progression in response to substrate biomechanical cues. First, we developed a unified image segmentation analysis, based on MATLAB algorithms, for the extraction of morphology parameters from subcellular structures, linked to biochemically identified cells from microscopy images. Second, we developed a multivariate logistic regression model for fitting RG probability based in nuclear morphology parameters and cell density. The application of this model to our experimental data revealed the existence of intrinsic RG nuclear constraints, and that nuclear deformation and changes in nuclear lamins ratio precedes the expression of NSC/RG markers. Third, by using pharmacological inhibitors and Ca2+ imaging, together with RG molecular markers, we determined the implication of excitatory and inhibitory mechanosensitive ion channels, changes in CaMKII activity and in intracellular calcium dynamics, in the biomechanical induction of RG. Fourth, we identified a metabolic switch from astrocyte to RG, involving changes in mitochondrial dynamics and a bias towards increased aerobic glycolysis and anabolic metabolism. Finally, the application of the RGM model to image datasets from mouse and human neural cells allows us to identify the evolutionary conservation of RG nuclear constraints. Converting our RGM model, and their future improved versions, into an invaluable tool with unsuspected possibilities for the analysis of brain development.
ca
dc.format.extent
255 p.
ca
dc.language.iso
eng
ca
dc.publisher
Universitat de Barcelona
dc.rights.license
ADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
ca
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Embriologia
ca
dc.subject
Embriología
ca
dc.subject
Embryology
ca
dc.subject
Neurobiologia del desenvolupament
ca
dc.subject
Neurobiología del desarrollo
ca
dc.subject
Developmental neurobiology
ca
dc.subject.other
Ciències de la Salut
ca
dc.title
Modeling the radial glia niche: Deciphering key mechanotransduction components
ca
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
616
ca
dc.contributor.director
Alcántara Horrillo, Soledad
dc.contributor.tutor
Alcántara Horrillo, Soledad
dc.embargo.terms
12 mesos
ca
dc.date.embargoEnd
2025-04-26T02:00:00Z
dc.rights.accessLevel
info:eu-repo/semantics/embargoedAccess


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