Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer's disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.
Authors
- Hayk Davtyan (ORCID: https://orcid.org/0000-0001-8554-6456)
- Jasmine Nguyen (ORCID: https://orcid.org/0000-0003-3227-2919)
- Jonathan Hasselmann (ORCID: https://orcid.org/0000-0003-2630-9850)
- Sepideh Kiani Shabestari (ORCID: https://orcid.org/0000-0002-2840-116X)
- William Carlen-Jones (ORCID: https://orcid.org/0009-0006-7486-4778)
- Christina Tu (ORCID: https://orcid.org/0000-0003-3904-2366)
- Mathew Blurton‐Jones (ORCID: https://orcid.org/0000-0002-7770-7157)
- Adrian Escobar (ORCID: https://orcid.org/0000-0003-2288-5789)
- Robert C. Spitale
- Joia Kai Capocchi (ORCID: https://orcid.org/0000-0002-3433-5904)
- Jean Paul Chadarevian (ORCID: https://orcid.org/0000-0002-2478-6592)
- Ghazaleh Eskandari‐Sedighi (ORCID: https://orcid.org/0000-0003-0447-7722)
- Malek Mansour (ORCID: https://orcid.org/0000-0001-8814-6431)
- Lauren Le (ORCID: https://orcid.org/0009-0006-8527-4554)
- Alina L Chadarevian
- Ekaterina Deynega
- Michael Mgerian
- Talar Chadarevian
Institutions
- University of California, Irvine (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1016/j.stem.2025.03.009
- Citations
- 33
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 26.95
Funders
- California Institute for Regenerative Medicine
- Larry L. Hillblom Foundation
- California Institute of Regenerative Medicine
- Cure Alzheimer's Fund
- Alzheimer Society
- National Institutes of Health
- National Institute on Aging
- National Institute on Drug Abuse