title: Busulfan conditioning enhances engraftment of hematopoietic donor-derived cells in the brain compared with irradiation.
abstract: Hematopoietic stem cell gene therapy for neurological disorders relies on transmigration of donor-derived monocytes to the brain, where they can engraft as microglia and deliver therapeutic proteins. Many mouse studies use whole-body irradiation to investigate brain transmigration pathways, but chemotherapy is generally used clinically. The current evidence for transmigration to the brain after chemotherapy is conflicting. We compared hematopoietic donor cell brain engraftment after bone marrow (BM) transplants in busulfan- or irradiation-conditioned mice. Significantly more donor-derived microglial cells engrafted posttransplant in busulfan-conditioned brain compared with the irradiated, in both the short and long term. Although total Iba-1(+) microglial content was increased in irradiated brain in the short term, it was similar between groups over long-term engraftment. MCP-1, a key regulator of monocyte transmigration, showed long-term elevation in busulfan-conditioned brain, whereas irradiated brains showed long-term elevation of the proinflammatory chemokine interleukin 1α (IL-1α), with increased in situ proliferation of resident microglia, and significant increases in the relative number of amoeboid activated microglia in the brain. This has implications for the choice of conditioning regimen to promote hematopoietic cell brain engraftment and the relevance of irradiation in mouse models of transplantation.
authors: Stem Cell and Neurotherapies, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors: Fiona L
authors: FL
authors: Wilkinson
authors: Ana
authors: A
authors: Sergijenko
authors: Kia J
authors: KJ
authors: Langford-Smith
authors: Marcela
authors: M
authors: Malinowska
authors: Rob F
authors: RF
authors: Wynn
authors: Brian W
authors: BW
authors: Bigger
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D002066:Busulfan / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007375:Interleukin-1; D002066:Busulfan