Microglia replacement by peripheral delivery of CSF1R inhibitor-resistant hematopoietic cells
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<sup>+</sup> G793A donor cells, engraftment is inconsistent and variable. Rag1-deficient hosts or GFP<sup>-</sup> 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.
Authors
- Christopher A. Hunter (ORCID: https://orcid.org/0000-0003-3092-1428)
- Michael S. Haney (ORCID: https://orcid.org/0000-0001-7381-4054)
- V Sai Chaluvadi (ORCID: https://orcid.org/0000-0002-0055-149X)
- Carleigh A. O’Brien (ORCID: https://orcid.org/0000-0003-4549-0640)
- Hayk Davtyan (ORCID: https://orcid.org/0000-0001-8554-6456)
- Kelsey M Nemec (ORCID: https://orcid.org/0000-0003-3036-254X)
- Fazeela Yaqoob (ORCID: https://orcid.org/0000-0002-9058-9810)
- William H. Aisenberg (ORCID: https://orcid.org/0000-0002-8715-1439)
- Megan M. Davis (ORCID: https://orcid.org/0000-0003-4221-7876)
- Emily Church (ORCID: https://orcid.org/0000-0002-7747-3549)
- Freddy S Purnell (ORCID: https://orcid.org/0000-0001-5060-8485)
- Mathew Blurton‐Jones (ORCID: https://orcid.org/0000-0002-7770-7157)
- Asif A. Dar (ORCID: https://orcid.org/0000-0002-0060-6200)
- Sangeeta Shukla (ORCID: https://orcid.org/0000-0002-3727-9602)
- Sonia I Lombroso (ORCID: https://orcid.org/0000-0003-2348-0417)
- Will Bailis (ORCID: https://orcid.org/0000-0001-9420-6250)
- Chet Oon (ORCID: https://orcid.org/0000-0002-1494-6628)
- Esha Banerjee (ORCID: https://orcid.org/0000-0001-7677-3702)
- F. Chris Bennett (ORCID: https://orcid.org/0000-0003-2570-0620)
- Jean Paul Chadarevian (ORCID: https://orcid.org/0000-0002-2478-6592)
- Stefano Arcangeli (ORCID: https://orcid.org/0000-0003-3880-8876)
- Charles‐Antoine Assenmacher (ORCID: https://orcid.org/0000-0003-0073-2730)
- Robin L. Anderson (ORCID: https://orcid.org/0000-0002-6841-7422)
- Daniel A Shapiro (ORCID: https://orcid.org/0000-0002-1289-8036)
- Brian Temsamrit
- Bilal Elfayoumi
- Yixuan Zhu (ORCID: https://orcid.org/0000-0001-8901-9741)
- Eli M Levitt
- Jessie Axsom
Institutions
- Children's Hospital of Philadelphia (US)
- University of California, Irvine (US)
- Hospital of the University of Pennsylvania (US)
- Parker Institute for Cancer Immunotherapy (US)
- Translational Therapeutics (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1016/j.ymthe.2025.10.050
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00