Publication: Chaperone-mediated autophagy sustains pericyte stemness necessary for brain tissue homeostasis
Authors
Martínez, Carlos M. ; Martínez-Morga, Marta ; Rodríguez-Madoz, Juan R. ; Prósper, Felipe ; Zapata, Agustín G. ; Moraleda, José María ; Martínez, Salvador ; García Bernal, David ; Roca Soler, Francisco José ; Salinas Hidalgo, María Dolores ; Valdor Alonso, Rut
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Publisher
Elsevier
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DOI
https://doi.org/10.1016/j.jare.2025.04.015
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info:eu-repo/semantics/article
Description
© 2025 The Authors. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. This document is the Accepted version of a Published Work that appeared in final form in Journal of Advanced Research. To access the final edited and published work see https://doi.org/10.1016/j.jare.2025.04.015
Abstract
Introduction: Pericytes (PCs) are mural cells exhibiting some mesenchymal stem cell (MSC) properties and contribute to tissue regeneration after injury. We have previously shown that glioblastoma cancer cells induce in PCs, a pathogenic upregulation of chaperone-mediated autophagy (CMA) which modulates immune functions and MSC-like properties to support tumor growth. Objectives: The aim of the study was to interrogate the role of CMA-regulated MSC properties in PCs in the context of tissue repair during inflammation triggered by a demyelinating injury. Methods: Studies of RNA-seq were done PCs with (WT) and without (LAMP-2A KO) CMA. Cell characterization related to stemness, lineage and morphology was done in WT and KO PCs. Secretome analysis and cell differentiation assay using the supernatants from CMA-efficient and deficient PCs cultures was done in mesenchymal cells. Inflammatory response of brain cells was assessed with WT and KO PCs secretome. To corroborate in vitro results, CMA modulation in response to inflammation in PCs and tissue repair markers were measured in the lesion areas of a demyelination mouse model and correlated with the tissue reparation after intravenous PC administration. An inflammatory mediator was used to study effects on PC-CMA activity.
Results
We found that inflammatory mediators such as IFNγ downregulate CMA in PCs, suppressing PC stemness and promoting a pro-inflammatory secretome. Restoration of PC CMA activity during inflammation maintains PC MSC properties and induces an MSC-like proteome which decreases inflammation and promotes tissue repair. We identified secreted proteins involved in regenerative and protective processes, and therefore, necessary to restore brain tissue homeostasis after inflammation induced by a demyelinating injury. Conclusion: we show that manipulation of CMA activity in host PCs could be a useful therapeutical approach in the context of brain inflammation, which might be extended to other diseases where the pericyte has a key role in response to inflammation.
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Citation
Journal of Advanced Research, 2025
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