Busulfan conditioning enhances engraftment of hematopoietic donor-derived cells in the brain compared with irradiation

Fiona L Wilkinson, Ana Sergijenko, Kia J Langford-Smith, Marcela Malinowska, Rob F Wynn, Brian W Bigger

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)868-876
Number of pages9
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume21
Issue number4
Early online date19 Feb 2013
DOIs
Publication statusPublished - Apr 2013

Keywords

  • animals
  • bone marrow transplantation
  • brain
  • busulfan
  • chemokine CCL2
  • hematopoietic stem cells
  • interleukin-1
  • mice
  • transplantation conditioning
  • whole-body irradiation

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