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Sci Adv. 2017 Dec 6;3(12):e1701211. doi: 10.1126/sciadv.1701211. eCollection 2017 Dec.

Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells.

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San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cell and Gene Therapy, San Raffaele Scientific Institute, Milano, Italy.
Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milano, Italy.
Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Program in Cellular and Molecular Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Gene Therapy Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.


Recent evidence indicates that hematopoietic stem and progenitor cells (HSPCs) can serve as vehicles for therapeutic molecular delivery to the brain by contributing to the turnover of resident myeloid cell populations. However, such engraftment needs to be fast and efficient to exert its therapeutic potential for diseases affecting the central nervous system. Moreover, the nature of the cells reconstituted after transplantation and whether they could comprise bona fide microglia remain to be assessed. We demonstrate that transplantation of HSPCs in the cerebral lateral ventricles provides rapid engraftment of morphologically, antigenically, and transcriptionally dependable microglia-like cells. We show that the cells comprised within the hematopoietic stem cell compartment and enriched early progenitor fractions generate this microglia-like population when injected in the brain ventricles in the absence of engraftment in the bone marrow. This delivery route has therapeutic relevance because it increases the delivery of therapeutic molecules to the brain, as shown in a humanized animal model of a prototypical lysosomal storage disease affecting the central nervous system.

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