CNS Repopulation by Hematopoietic-Derived Microglia-Like Cells Corrects Progranulin deficiency.

Autor:	Colella P; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305., Sayana R; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305., Suarez-Nieto MV; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305., Sarno J; Hematology, Oncology, Stem Cell Transplant, and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, 94305., Nyame K; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Department of Genetics, Stanford University, Stanford, CA 94305., Xiong J; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Department of Genetics, Stanford University, Stanford, CA 94305., Vera LNP; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305., Basurto JA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305., Corbo M; MedGenome, Inc, 348 Hatch Dr, Foster City, CA 94404., Limaye A; MedGenome, Inc, 348 Hatch Dr, Foster City, CA 94404., Davis KL; Hematology, Oncology, Stem Cell Transplant, and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, 94305., Abu-Remaileh M; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Department of Genetics, Stanford University, Stanford, CA 94305.; The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, USA., Gomez-Ospina N; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Sep 12. Date of Electronic Publication: 2023 Sep 12.
DOI:	10.21203/rs.3.rs-3263412/v1
Abstrakt:	Hematopoietic stem cell transplantation can deliver therapeutic proteins to the CNS through donor-derived hematopoietic cells that become microglia-like cells. However, using standard conditioning approaches, hematopoietic stem cell transplantation is currently limited by low and slow engraftment of microglia-like cells. We report an efficient conditioning regimen based on Busulfan and a six-day course of microglia depletion using the colony-stimulating factor receptor 1 inhibitor PLX3397. Combining Busulfan-myeloablation and transient microglia depletion results in robust, rapid, and persistent microglia replacement by bone marrow-derived microglia-like cells throughout the CNS. Adding PLX3397 does not affect neurobehavior or has adverse effects on hematopoietic reconstitution. Through single-cell RNA sequencing and high-dimensional CyTOF mass cytometry, we show that microglia-like cells are a heterogeneous population and describe six distinct subpopulations. Though most bone-marrow-derived microglia-like cells can be classified as homeostatic microglia, their gene signature is a hybrid of homeostatic/embryonic microglia and border associated-macrophages. Busulfan-myeloablation and transient microglia depletion induce specific cytokines in the brain, ultimately combining myeloid proliferative and chemo-attractive signals that act locally to repopulate microglia from outside the niche. Importantly, this conditioning approach demonstrates therapeutic efficacy in a mouse model of GRN deficiency. Transplanting wild-type bone marrow into Grn -/- mice conditioned with Busulfan plus PLX3397 results in high engraftment of microglia-like cells in the brain and retina, restoring GRN levels and normalizing lipid metabolism.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu