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@ARTICLE{Shibuya:163738,
author = {Shibuya, Yohei and Kumar, Kevin K and Mader, Marius
Marc-Daniel and Yoo, Yongjin and Ayala, Luis Angel and Zhou,
Mu and Mohr, Manuel Alexander and Neumayer, Gernot and
Kumar, Ishan and Yamamoto, Ryo and Marcoux, Paul and Liou,
Benjamin and Bennett, F Chris and Nakauchi, Hiromitsu and
Sun, Ying and Chen, Xiaoke and Heppner, Frank and
Wyss-Coray, Tony and Südhof, Thomas C and Wernig, Marius},
title = {{T}reatment of a genetic brain disease by {CNS}-wide
microglia replacement.},
journal = {Science translational medicine},
volume = {14},
number = {636},
issn = {1946-6234},
address = {Washington, DC},
publisher = {AAAS},
reportid = {DZNE-2022-00477},
pages = {eabl9945},
year = {2022},
abstract = {Hematopoietic cell transplantation after myeloablative
conditioning has been used to treat various genetic
metabolic syndromes but is largely ineffective in diseases
affecting the brain presumably due to poor and variable
myeloid cell incorporation into the central nervous system.
Here, we developed and characterized a near-complete and
homogeneous replacement of microglia with bone marrow cells
in mice without the need for genetic manipulation of donor
or host. The high chimerism resulted from a competitive
advantage of scarce donor cells during microglia
repopulation rather than enhanced recruitment from the
periphery. Hematopoietic stem cells, but not immediate
myeloid or monocyte progenitor cells, contained full
microglia replacement potency equivalent to whole bone
marrow. To explore its therapeutic potential, we applied
microglia replacement to a mouse model for Prosaposin
deficiency, which is characterized by a progressive
neurodegeneration phenotype. We found a reduction of
cerebellar neurodegeneration and gliosis in treated brains,
improvement of motor and balance impairment, and life span
extension even with treatment started in young adulthood.
This proof-of-concept study suggests that efficient
microglia replacement may have therapeutic efficacy for a
variety of neurological diseases.},
keywords = {Animals / Bone Marrow Cells / Brain / Brain Diseases /
Central Nervous System / Hematopoietic Stem Cell
Transplantation / Mice / Microglia},
cin = {AG Heppner},
ddc = {500},
cid = {I:(DE-2719)1810007},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9618306},
pubmed = {pmid:35294256},
doi = {10.1126/scitranslmed.abl9945},
url = {https://pub.dzne.de/record/163738},
}