2. Academic Validation
  3. CSF1R inhibitor-resistant model for CNS-wide microglia replacement strategies

CSF1R inhibitor-resistant model for CNS-wide microglia replacement strategies

  • Mol Ther. 2025 Nov 12:S1525-0016(25)00872-X. doi: 10.1016/j.ymthe.2025.10.051.
Jean Paul Chadarevian 1,  Jasmine Nguyen 2,  Lauren Le 3,  L Angel Ayala 4,  Alina L Chadarevian 1,  Cuiwen Zhou 5,  Adrian Escobar 6,  Abby T Do 6,  Ekaterina Deynega 3,  Kimiya Mansour 7,  Jonathan Hasselmann 6,  Ghazaleh Eskandari-Sedighi 3,  Sonia I Lombroso 8,  F Chris Bennett 9,  Matthew A Inlay 4,  Hayk Davtyan 10,  Mathew Blurton-Jones 11
Affiliations

Affiliations

  • 1 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 2 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
  • 3 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
  • 4 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 5 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 6 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 7 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 8 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 10 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 11 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: [email protected].
PMID: 41232524 DOI: 10.1016/j.ymthe.2025.10.051
Abstract

Recent advances in cell-based therapies have demonstrated therapeutic safety and efficacy for a variety of diseases. However, significant challenges remain in their development for the treatment of neurological disorders. Preclinical studies have explored microglial replacement strategies utilizing bone marrow transplantation and CSF1R inhibitor (CSF1Ri) treatment. However, these approaches often require highly invasive strategies and result in engrafted cells that remain transcriptionally and functionally distinct from microglia. To assess less-invasive microglia replacement strategies capable of preserving microglial ontogeny, we developed a Csf1r-G793A knockin mouse. We found that G793A mice develop typical microglial densities and peripheral hematopoietic populations, which exhibit broad CSF1Ri resistance enabling widespread microglia replacement following direct intraparenchymal injection or bone marrow transplantation. Furthermore, we demonstrate that widespread microglia replacement can be achieved via less-invasive intracisternal delivery of CSF1Ri-resistant murine and induced pluripotent stem cell (iPSC)-derived human microglia. Together with the accompanying study by Lombroso and colleagues, our findings demonstrate that G793A mice provide a robust and broadly applicable source of engraftable donor microglia and peripheral macrophages for the preclinical investigation of microglia replacement strategies.

Keywords

CSF1R inhibitors; cell therapies; iPSC-microglia; immune cell therapy; microglia; microglia replacement; microglia transplantation; routes of delivery.

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