| First Author | Skinner AM | Year | 2008 |
| Journal | Exp Hematol | Volume | 36 |
| Issue | 3 | Pages | 273-82 |
| PubMed ID | 18279715 | Mgi Jnum | J:132714 |
| Mgi Id | MGI:3776715 | Doi | 10.1016/j.exphem.2007.11.006 |
| Citation | Skinner AM, et al. (2008) CXCR4 induction in hematopoietic progenitor cells from Fanca(-/-), -c(-/-), and -d2(-/-) mice. Exp Hematol 36(3):273-82 |
| abstractText | 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. |
