Engineering an inhibitor-resistant human CSF1R variant for microglia replacement.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 03 2023
06 03 2023
Historique:
received:
15
05
2022
revised:
11
11
2022
accepted:
13
12
2022
entrez:
30
12
2022
pubmed:
31
12
2022
medline:
4
1
2023
Statut:
ppublish
Résumé
Hematopoietic stem cell transplantation (HSCT) can replace endogenous microglia with circulation-derived macrophages but has high mortality. To mitigate the risks of HSCT and expand the potential for microglia replacement, we engineered an inhibitor-resistant CSF1R that enables robust microglia replacement. A glycine to alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors, including PLX3397 and PLX5622. Biochemical and cell-based assays show no discernable gain or loss of function. G795A- but not wildtype-CSF1R expressing macrophages efficiently engraft the brain of PLX3397-treated mice and persist after cessation of inhibitor treatment. To gauge translational potential, we CRISPR engineered human-induced pluripotent stem cell-derived microglia (iMG) to express G795A. Xenotransplantation studies demonstrate that G795A-iMG exhibit nearly identical gene expression to wildtype iMG, respond to inflammatory stimuli, and progressively expand in the presence of PLX3397, replacing endogenous microglia to fully occupy the brain. In sum, we engineered a human CSF1R variant that enables nontoxic, cell type, and tissue-specific replacement of microglia.
Identifiants
pubmed: 36584406
pii: 213788
doi: 10.1084/jem.20220857
pii:
doi:
Substances chimiques
Aminopyridines
0
Csf1r protein, mouse
0
pexidartinib
6783M2LV5X
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : S10 OD021718
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG073088
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR025496
Pays : United States
Organisme : NIMH NIH HHS
ID : T32 MH014654
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061895
Pays : United States
Organisme : NIH HHS
ID : S10 OD010794
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008076
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS120960
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066519
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007170
Pays : United States
Organisme : NIGMS NIH HHS
ID : K12 GM081259
Pays : United States
Organisme : NIDA NIH HHS
ID : RF1 DA048813
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 Chadarevian et al.
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