Human microglial cells as a therapeutic target in a neurodevelopmental disease model.

Autor:	Mesci P; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA. Electronic address: pmesci@gmail.com., LaRock CN; Department of Pediatrics, University of California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92037, USA; Department of Microbiology and Immunology, Department of Medicine, Division of Infectious Diseases, Emory School of Medicine, Atlanta, GA 30322, USA., Jeziorski JJ; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Nakashima H; Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Chermont N; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Ferrasa A; Experimental Multiuser Laboratory (LEM), Graduate Program in Health Sciences (PPGCS), School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Paraná 80215-901, Brazil; Department of Informatics (DEINFO), Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, Paraná 84030-900, Brazil., Herai RH; Experimental Multiuser Laboratory (LEM), Graduate Program in Health Sciences (PPGCS), School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Paraná 80215-901, Brazil; Research Department, Lico Kaesemodel Institute (ILK), Curitiba, Paraná, Brazil., Ozaki T; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Saleh A; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Snethlage CE; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Sanchez S; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Goldberg G; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Trujillo CA; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA., Nakashima K; Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Nizet V; Department of Pediatrics, University of California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92037, USA., Muotri AR; University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA; University of California, San Diego, Kavli Institute for Brain and Mind, Center for Academic Research and Training in Anthropogeny (CARTA), La Jolla, CA 92093, USA. Electronic address: muotri@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2024 Aug 13; Vol. 19 (8), pp. 1074-1091. Date of Electronic Publication: 2024 Jul 25.
DOI:	10.1016/j.stemcr.2024.06.013
Abstrakt:	Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions. Competing Interests: Declaration of interests A.R.M. is a co-founder and has an equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis focusing on therapeutic applications customized for the disorder autism spectrum and other neurological disorders origin genetics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies. The authors have a patent application in works related to this publication. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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