CXCR4 induction in hematopoietic progenitor cells from Fanca-/-, -c-/-, and -d2-/- mice

Amy M. Skinner, S. Lee O'Neill, Markus Grompe, Peter Kurre

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Objective: Bone marrow failure is a near-universal occurrence in patients with Fanconi anemia (FA) and is thought to result from exhaustion of the hematopoietic stem cell (HSC) pool. Retrovirus-mediated expression of the deficient protein corrects this phenotype and makes FA a candidate disease for HSC-directed gene therapy. However, inherent repopulation deficits and stem cell attrition during conventional transduction culture prevent therapeutic chimerism. Materials and Methods: We previously reported rapid transduction protocols to limit stem cell losses after ex vivo culture. Here we describe a complementary strategy intended to improve repopulation through upregulation of chemokine receptor (CXCR) 4, a principal factor in hematopoietic homing. Results: Using murine models with transgenic disruption of Fanca, -c, and -d2, we found that c-kit+ and sca-1+ progenitor cells express levels of CXCR4 comparable with those of wild-type littermates. Lineage-depleted progenitor populations rapidly upregulated CXCR4 transcript and protein in response to cytokine stimulation or hypoxia, regardless of genotype. Hypoxia conditioning of lineage-depleted Fancc-/- progenitors also reduced oxidative stress, improved in vitro migration and led to improved chimerism in myeloablated recipients after transplantation. Conclusion: These studies provide evidence that CXCR4 regulation in progenitor cells from transgenic mice representing multiple FA genotypes is intact and that modulation of homing offers a potential strategy to offset the FA HSC repopulation deficiency.

Original languageEnglish (US)
Pages (from-to)273-282
Number of pages10
JournalExperimental hematology
Volume36
Issue number3
DOIs
StatePublished - Mar 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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