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Comment
. 2023 Mar 6;220(3):e20222070.
doi: 10.1084/jem.20222070. Epub 2023 Jan 17.

Engineering mighty microglia

Adeline E Walsh  1   2   3 , John R Lukens  1   2   3
Affiliations
Comment

Engineering mighty microglia

Adeline E Walsh et al. J Exp Med. .

Abstract

Defective microglial responses underlie many neurological disorders. Recent efforts to swap out dysfunctional microglia with optimized replacements have been derailed by safety issues and transplantation inefficiencies. In this issue, Chadarevian et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20220857) designed a novel strategy that enables improved engraftment of human microglia.

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Figures

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Insights from Adeline E. Walsh and John R. Lukens.
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Microglia engineered to harbor an inhibitor-resistant mutation in human CSF1R offer an improved strategy to replace faulty microglia in neurological diseases. (A) The current methods to deplete and replace microglia in humans involves HSCT. This method requires intense immunosuppressive pretreatments to promote engraftment, and the resulting peripheral macrophages and myeloid cells do not fully recapitulate endogenous microglia. (B) Microglia engineered to possess a G795A mutation in CSF1R successfully engraft the adult mouse brain and are resistant to subsequent CSF1R inhibitor (PLX3397) treatment, thus allowing for efficient replacement of microglia. The beneficial properties of these engineered microglia could potentially be bolstered by targeting other neurological disease–related genes such as TREM2, CD33, or PLCG2 in tandem.
See this image and copyright information in PMC

Comment on

  • Engineering an inhibitor-resistant human CSF1R variant for microglia replacement.
    Chadarevian JP, Lombroso SI, Peet GC, Hasselmann J, Tu C, Marzan DE, Capocchi J, Purnell FS, Nemec KM, Lahian A, Escobar A, England W, Chaluvadi S, O'Brien CA, Yaqoob F, Aisenberg WH, Porras-Paniagua M, Bennett ML, Davtyan H, Spitale RC, Blurton-Jones M, Bennett FC. Chadarevian JP, et al. J Exp Med. 2023 Mar 6;220(3):e20220857. doi: 10.1084/jem.20220857. Epub 2022 Dec 30. J Exp Med. 2023. PMID: 36584406 Free PMC article.

References

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