Modeling the radial glia niche: Deciphering key mechanotransduction components

[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 cons...

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Autor: Soriano Esqué, José Pablo
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/214658
Acceso en línea:https://hdl.handle.net/2445/214658
http://hdl.handle.net/10803/691845
Access Level:acceso abierto
Palabra clave:Embriologia
Neurobiologia del desenvolupament
Embryology
Developmental neurobiology
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spelling Modeling the radial glia niche: Deciphering key mechanotransduction componentsSoriano Esqué, José PabloEmbriologiaNeurobiologia del desenvolupamentEmbryologyDevelopmental neurobiology[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.Universitat de BarcelonaAlcántara Horrillo, SoledadUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/214658http://hdl.handle.net/10803/691845Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Soriano Esqué, José Pablo, 2024info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2146582026-05-27T06:46:51Z
dc.title.none.fl_str_mv Modeling the radial glia niche: Deciphering key mechanotransduction components
title Modeling the radial glia niche: Deciphering key mechanotransduction components
spellingShingle Modeling the radial glia niche: Deciphering key mechanotransduction components
Soriano Esqué, José Pablo
Embriologia
Neurobiologia del desenvolupament
Embryology
Developmental neurobiology
title_short Modeling the radial glia niche: Deciphering key mechanotransduction components
title_full Modeling the radial glia niche: Deciphering key mechanotransduction components
title_fullStr Modeling the radial glia niche: Deciphering key mechanotransduction components
title_full_unstemmed Modeling the radial glia niche: Deciphering key mechanotransduction components
title_sort Modeling the radial glia niche: Deciphering key mechanotransduction components
dc.creator.none.fl_str_mv Soriano Esqué, José Pablo
author Soriano Esqué, José Pablo
author_facet Soriano Esqué, José Pablo
author_role author
dc.contributor.none.fl_str_mv Alcántara Horrillo, Soledad
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Embriologia
Neurobiologia del desenvolupament
Embryology
Developmental neurobiology
topic Embriologia
Neurobiologia del desenvolupament
Embryology
Developmental neurobiology
description [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.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/214658
http://hdl.handle.net/10803/691845
url https://hdl.handle.net/2445/214658
http://hdl.handle.net/10803/691845
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Soriano Esqué, José Pablo, 2024
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Soriano Esqué, José Pablo, 2024
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Medicina i Ciències de la Salut
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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