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000163738 037__ $$aDZNE-2022-00477
000163738 041__ $$aEnglish
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000163738 1001_ $$00000-0002-8825-5440$$aShibuya, Yohei$$b0
000163738 245__ $$aTreatment of a genetic brain disease by CNS-wide microglia replacement.
000163738 260__ $$aWashington, DC$$bAAAS$$c2022
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000163738 520__ $$aHematopoietic 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.
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000163738 650_2 $$2MeSH$$aAnimals
000163738 650_2 $$2MeSH$$aBone Marrow Cells
000163738 650_2 $$2MeSH$$aBrain
000163738 650_2 $$2MeSH$$aBrain Diseases
000163738 650_2 $$2MeSH$$aCentral Nervous System
000163738 650_2 $$2MeSH$$aHematopoietic Stem Cell Transplantation
000163738 650_2 $$2MeSH$$aMice
000163738 650_2 $$2MeSH$$aMicroglia
000163738 7001_ $$00000-0002-0704-1492$$aKumar, Kevin K$$b1
000163738 7001_ $$00000-0002-7467-9672$$aMader, Marius Marc-Daniel$$b2
000163738 7001_ $$aYoo, Yongjin$$b3
000163738 7001_ $$00000-0002-6272-3314$$aAyala, Luis Angel$$b4
000163738 7001_ $$00000-0001-5326-4884$$aZhou, Mu$$b5
000163738 7001_ $$00000-0002-5189-541X$$aMohr, Manuel Alexander$$b6
000163738 7001_ $$aNeumayer, Gernot$$b7
000163738 7001_ $$00000-0001-6847-9706$$aKumar, Ishan$$b8
000163738 7001_ $$aYamamoto, Ryo$$b9
000163738 7001_ $$aMarcoux, Paul$$b10
000163738 7001_ $$aLiou, Benjamin$$b11
000163738 7001_ $$aBennett, F Chris$$b12
000163738 7001_ $$00000-0002-9841-6973$$aNakauchi, Hiromitsu$$b13
000163738 7001_ $$aSun, Ying$$b14
000163738 7001_ $$00000-0001-9032-9093$$aChen, Xiaoke$$b15
000163738 7001_ $$0P:(DE-2719)2812386$$aHeppner, Frank$$b16$$udzne
000163738 7001_ $$00000-0001-5893-0831$$aWyss-Coray, Tony$$b17
000163738 7001_ $$00000-0003-3361-9275$$aSüdhof, Thomas C$$b18
000163738 7001_ $$00000-0002-5309-515X$$aWernig, Marius$$b19
000163738 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.abl9945$$gVol. 14, no. 636, p. eabl9945$$n636$$peabl9945$$tScience translational medicine$$v14$$x1946-6234$$y2022
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