Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo.
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ metabolism
Animals
Brain
/ cytology
Cell Differentiation
Disease Models, Animal
Gene Expression
Granulocyte-Macrophage Colony-Stimulating Factor
/ genetics
Hematopoietic Stem Cell Transplantation
Humans
Induced Pluripotent Stem Cells
/ cytology
Macrophage Colony-Stimulating Factor
/ genetics
Mice
Mice, Transgenic
Microglia
/ cytology
Plaque, Amyloid
/ genetics
Thrombopoietin
/ genetics
Transplantation Chimera
Alzheimer’s disease
TREM-2
beta-amyloid
chimera
hematopoietic
humanized
microglia
neurodegeneration
pluripotent
stem cells
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
25 09 2019
25 09 2019
Historique:
received:
15
01
2019
revised:
10
06
2019
accepted:
28
06
2019
pubmed:
4
8
2019
medline:
25
3
2020
entrez:
4
8
2019
Statut:
ppublish
Résumé
iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.
Identifiants
pubmed: 31375314
pii: S0896-6273(19)30600-2
doi: 10.1016/j.neuron.2019.07.002
pmc: PMC7138101
mid: NIHMS1563396
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
CSF1 protein, human
0
CSF2 protein, human
0
Macrophage Colony-Stimulating Factor
81627-83-0
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Thrombopoietin
9014-42-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
1016-1033.e10Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008620
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG048099
Pays : United States
Organisme : NIGMS NIH HHS
ID : DP2 GM119164
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS109200
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000096
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061895
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG055524
Pays : United States
Organisme : NIDA NIH HHS
ID : RF1 DA048813
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028212
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NEI NIH HHS
ID : F30 EY029596
Pays : United States
Organisme : NIH HHS
ID : S10 OD021718
Pays : United States
Organisme : NEI NIH HHS
ID : F31 EY028046
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS082174
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056303
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR025496
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG016573
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS096170
Pays : United States
Organisme : NIH HHS
ID : S10 OD010794
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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