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.
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.
Authors: T Ponomaryov; A Peled; I Petit; R S Taichman; L Habler; J Sandbank; F Arenzana-Seisdedos; A Magerus; A Caruz; N Fujii; A Nagler; M Lahav; M Szyper-Kravitz; D Zipori; T Lapidot Journal: J Clin Invest Date: 2000-12 Impact factor: 14.808
Authors: J M Croop; R Cooper; C Fernandez; V Graves; S Kreissman; H Hanenberg; F O Smith; D A Williams Journal: Blood Date: 2001-11-15 Impact factor: 22.113
Authors: Dao Pan; Roland Gunther; Weiming Duan; Steve Wendell; William Kaemmerer; Tal Kafri; Inder M Verma; Chester B Whitley Journal: Mol Ther Date: 2002-07 Impact factor: 11.454
Authors: Brandon K Wyss; Abigail F W Donnelly; Dan Zhou; Anthony L Sinn; Karen E Pollok; W Scott Goebel Journal: Exp Hematol Date: 2009-07 Impact factor: 3.084
Authors: Young Me Yoon; Kelsie J Storm; Ashley N Kamimae-Lanning; Natalya A Goloviznina; Peter Kurre Journal: Stem Cell Reports Date: 2016-10-06 Impact factor: 7.765