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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 2008

Fingerprint

Fanconi Anemia
Hematopoietic Stem Cells
Stem Cells
Chimerism
Genotype
Chemokine Receptors
Retroviridae
Genetic Therapy
Transgenic Mice
Proteins
Oxidative Stress
Up-Regulation
Transplantation
Bone Marrow
Cytokines
Phenotype
Population
Hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

CXCR4 induction in hematopoietic progenitor cells from Fanca-/-, -c-/-, and -d2-/- mice. / Skinner, Amy; O'Neill, S. Lee; Grompe, Markus; Kurre, Peter.

In: Experimental Hematology, Vol. 36, No. 3, 03.2008, p. 273-282.

Research output: Contribution to journalArticle

@article{741d596ed05541d29c59a429f904a4ae,
title = "CXCR4 induction in hematopoietic progenitor cells from Fanca-/-, -c-/-, and -d2-/- mice",
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.",
author = "Amy Skinner and O'Neill, {S. Lee} and Markus Grompe and Peter Kurre",
year = "2008",
month = "3",
doi = "10.1016/j.exphem.2007.11.006",
language = "English (US)",
volume = "36",
pages = "273--282",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - CXCR4 induction in hematopoietic progenitor cells from Fanca-/-, -c-/-, and -d2-/- mice

AU - Skinner, Amy

AU - O'Neill, S. Lee

AU - Grompe, Markus

AU - Kurre, Peter

PY - 2008/3

Y1 - 2008/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=38949138812&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38949138812&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2007.11.006

DO - 10.1016/j.exphem.2007.11.006

M3 - Article

C2 - 18279715

AN - SCOPUS:38949138812

VL - 36

SP - 273

EP - 282

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 3

ER -