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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4944-4953.
Prepublished online as a Blood First Edition Paper on February 5, 2008; DOI 10.1182/blood-2007-11-124644.
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Submitted November 29, 2007
Accepted January 30, 2008
Modulation of murine embryonic stem cell-derived CD41+c-kit+ hematopoietic progenitors by ectopic expression of Cdx genes
Shannon L McKinney-Freeman, Claudia Lengerke, Il-Ho Jang, Sabine Schmitt, Yuan Wang, Marsha Philitas, and George Q. Daley*
Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA, United States
University of Tuebingen Medical Center II, Tuebingen, Germany
Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
Harvard Stem Cell Institute, Cambridge, MA, United States
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
* Corresponding author; email: george.daley{at}childrens.harvard.edu.
Cdx1, Cdx2 and Cdx4 comprise the caudal-like Cdx gene family in mammals, whose homologues regulate hematopoietic development in zebrafish. Previously, we reported that over-expression of Cdx4 enhances hematopoietic potential from murine embryonic stem cells (ESC). Here we compare the effect of ectopic Cdx1, Cdx2, and Cdx4 on the differentiation of ESC-derived hematopoietic progenitors. The three Cdx genes differentially influence the formation and differentiation of hematopoietic progenitors within a CD41+c-kit+ population of embryoid body (EB)-derived cells. Cdx1 and Cdx4 enhance, while Cdx2 strongly inhibits, the hematopoietic potential of CD41+ckit+ EB-derived cells, changes that are reflected by effects on hematopoietic lineage-specific and Hox gene expression. When we subject stromal cell and colony assay cultures of EB-derived hematopoietic progenitors to ectopic expression of Cdx genes, Cdx4 dramatically enhances, while Cdx1 and Cdx2 both inhibit hematopoietic activity, likely by blocking progenitor differentiation. These data demonstrate distinct effects of Cdx genes on hematopoietic progenitor formation and differentiation, insights that we are using to facilitate efforts at in vitro culture of hematopoietic progenitors from ESC. The behavior of Cdx genes in vitro suggests how derangement of these developmental regulators might contribute to leukemogenesis.
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