2. Academic Validation
  3. Microglia replacement by peripheral delivery of CSF1R inhibitor-resistant hematopoietic cells

Microglia replacement by peripheral delivery of CSF1R inhibitor-resistant hematopoietic cells

  • Mol Ther. 2026 Feb 4;34(2):850-866. doi: 10.1016/j.ymthe.2025.10.050.
Sonia I Lombroso 1,  Emily I Church 2,  Ryan N Anderson 3,  Carleigh A O'Brien 2,  Yixuan Zhu 4,  Asif A Dar 5,  Freddy S Purnell 6,  Eli M Levitt 2,  Brian Temsamrit 5,  Fazeela Yaqoob 2,  William H Aisenberg 2,  Mara Davis 7,  Bilal Elfayoumi 2,  Sai Chaluvadi 8,  Kelsey M Nemec 8,  Jessie Axsom 9,  Daniel A Shapiro 10,  Chet Huan Oon 11,  Jean Paul Chadarevian 12,  Charles-Antoine Assenmacher 13,  Stefano De Arcangeli 14,  Esha Banerjee 13,  Sangeeta Shukla 15,  Hayk Davtyan 16,  Will Bailis 17,  Christopher A Hunter 18,  Mathew Blurton-Jones 12,  Mariko L Bennett 19,  Michael S Haney 4,  F Chris Bennett 20
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 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; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 6 Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia PA 19104, USA.
  • 8 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 10 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 11 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia PA 19104, USA.
  • 12 Department of Neurobiology and 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.
  • 13 Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
  • 14 Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 15 Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 16 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.
  • 17 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 18 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 19 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 20 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; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 41232525 DOI: 10.1016/j.ymthe.2025.10.050
Abstract

Microglia replacement holds great promise for the study and treatment of neurological diseases. We previously achieved high-efficiency replacement by engineering an inhibitor-resistant human CSF1R variant, G795A. Here and in Chadarevian et al, we introduce a transgenic mouse line carrying the homologous murine inhibitor resistance mutation, G793A. G793A confers resistance to CSF1R inhibitors (CSF1Ris) without impacting cell or organismal function, allowing brain-wide microglia replacement after intravascular delivery of myeloid cells or progenitors. G793A macrophages have normal CSF1R signaling and effector responses in cell-based assays. CSF1Ri treatment paired with peripheral vascular delivery of G793A myeloid cells, including ex vivo expanded hematopoietic stem cells, leads to microglia replacement in neonates and adults, with low peripheral chimerism. With vascular adoptive transfer of GFP+ G793A donor cells, engraftment is inconsistent and variable. Rag1-deficient hosts or GFP- donor cells, however, led to robust replacement of virtually all microglia, suggesting that G793A-based microglia replacement substantially spares host adaptive immune function. Although equally efficient, microglia replacement using G793A donors is less toxic to neuronal and oligodendrocyte progenitors than traditional hematopoietic stem cell transplantation. We present an approach for robust, reduced toxicity microglia replacement by intravenous adoptive transfer using a new research tool, the G793A mouse.

Keywords

CSF1R; microglia; microglia replacement; myeloid cell therapies; neuroimmunology; stem cell transplantation.

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