Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 37; pp. 15018 - 15023
• Main Authors: Capotondo, Alessia, Milazzo, Rita, Politi, Letterio Salvatore, Quattrini, Angelo, Palini, Alessio, Plati, Tiziana, Merella, Stefania, Nonis, Alessandro, di Serio, Clelia, Montini, Eugenio, Naldini, Luigi, Biffi, Alessandra
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.09.2012; National Acad Sciences
• Subjects: Analysis of Variance; Animals; Biological Sciences; Brain; brain waves; Cell Differentiation - physiology; Cell Movement - physiology; Cell transplantation; Central nervous system; Chimerism; Flow Cytometry; Green Fluorescent Proteins - metabolism; Hematocrit; Hematopoietic Stem Cell Transplantation - methods; immigration; In Situ Nick-End Labeling; Lysosomal Storage Diseases, Nervous System - therapy; Mice; Mice, Knockout; Microglia; Microglia - cytology; monocytes; Myeloid cells; Myeloid progenitor cells; nervous system diseases; neuroglia; Rodents; Stem cells; Transplantation; Transplantation Conditioning - methods; Transplants & implants
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1205858109

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.