2. Academic Validation
  3. Human microglial cells as a therapeutic target in a neurodevelopmental disease model

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

  • Stem Cell Reports. 2024 Aug 13;19(8):1074-1091. doi: 10.1016/j.stemcr.2024.06.013.
Pinar Mesci 1,  Christopher N LaRock 2,  Jacob J Jeziorski 3,  Hideyuki Nakashima 4,  Natalia Chermont 3,  Adriano Ferrasa 5,  Roberto H Herai 6,  Tomoka Ozaki 3,  Aurian Saleh 3,  Cedric E Snethlage 3,  Sandra Sanchez 3,  Gabriela Goldberg 3,  Cleber A Trujillo 3,  Kinichi Nakashima 4,  Victor Nizet 7,  Alysson R Muotri 8
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 5 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.
  • 6 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.
  • 7 Department of Pediatrics, University of California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92037, USA.
  • 8 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.
PMID: 39059378 DOI: 10.1016/j.stemcr.2024.06.013
Abstract

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.

Keywords

ADH-503; CD11b; MECP2; chromatin; iPSC; integrin; microglia; neurodevelopment; neurons; phagocytosis; stem cells; synaptogenesis.

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