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Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.
Chadarevian, Jean Paul; Hasselmann, Jonathan; Lahian, Alina; Capocchi, Joia K; Escobar, Adrian; Lim, Tau En; Le, Lauren; Tu, Christina; Nguyen, Jasmine; Kiani Shabestari, Sepideh; Carlen-Jones, William; Gandhi, Sunil; Bu, Guojun; Hume, David A; Pridans, Clare; Wszolek, Zbigniew K; Spitale, Robert C; Davtyan, Hayk; Blurton-Jones, Mathew.
Afiliação
  • Chadarevian JP; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, US
  • Hasselmann J; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Lahian A; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, US
  • Capocchi JK; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • Escobar A; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Lim TE; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Le L; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • Tu C; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Nguyen J; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • Kiani Shabestari S; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
  • Carlen-Jones W; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
  • Gandhi S; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
  • Bu G; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.
  • Hume DA; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
  • Pridans C; University of Edinburgh, University of Edinburgh Center for Inflammation Research, Edinburgh, UK.
  • Wszolek ZK; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
  • Spitale RC; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
  • Davtyan H; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA. Electronic address: hdavtyan@uci.edu.
  • Blurton-Jones M; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, US
Neuron ; 2024 Jun 12.
Article em En | MEDLINE | ID: mdl-38897209
ABSTRACT
Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos