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CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice
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CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice
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Journal Article
CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice
2024
Overview
Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.
Progranulin deficiency causes untreatable neurodegenerative diseases. Here, the authors show that hematopoietic stem cell transplantation and optimized brain conditioning correct the disease phenotype in progranulin-deficient mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/21
/ 13/31
/ 13/51
/ 14/35
/ 14/63
/ 38/91
/ 64/60
/ 82/1
/ 82/51
/ 82/58
/ 82/80
/ Aminopyridines - pharmacology
/ Animals
/ Brain
/ Busulfan
/ Central Nervous System - metabolism
/ Hematopoietic Stem Cell Transplantation
/ Hematopoietic Stem Cells - cytology
/ Hematopoietic Stem Cells - drug effects
/ Hematopoietic Stem Cells - metabolism
/ Humanities and Social Sciences
/ Lipids
/ Macrophage colony-stimulating factor
/ Male
/ Mice
/ Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors
/ Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics
/ Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
/ Science
