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

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 hematopo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (37), p.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: Article
Language:English
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1205858109