The cdx-hox pathway in hematopoietic stem cell formation from embryonic stem cells.
Embryonic stem cells (ESCs) differentiated in vitro will yield a multitude of hematopoietic derivatives, yet progenitors displaying true stem cell activity remain difficult to obtain. Possible causes are a biased differentiation to primitive yolk sac-type hematopoiesis, and a variety of developmental or functional deficiencies. Recent studies in the zebrafish have identified the caudal homeobox transcription factors (cdx1/4) and posterior hox genes (hoxa9a, hoxb7a) as key regulators for blood formation during embryonic development. Activation of Cdx and Hox genes during the in vitro differentiation of mouse ESCs followed by co-culture on supportive stromal cells generates ESC-derived hematopoietic stem cells (HSCs) capable of multilineage repopulation of lethally irradiated adult mice. We show here that brief pulses of ectopic Cdx4 or HoxB4 expression are sufficient to enhance hematopoiesis during ESC differentiation, presumably by acting as developmental switches to activate posterior Hox genes. Insights into the role of the Cdx-Hox gene pathway during embryonic hematopoietic development in the zebrafish have allowed us to improve the derivation of repopulating HSCs from murine ESCs.
Lengerke
Claudia
C
Division of Pediatric Hematology/Oncology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
McKinney-Freeman
Shannon
S
Naveiras
Olaia
O
Yates
Frank
F
Wang
Yuan
Y
Bansal
Dimple
D
Daley
George Q
GQ
D000818:Animals; D019521:Body Patterning; D002469:Cell Separation; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism*
C084563:Cdx4 protein, mouse; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D040201:Platelet Membrane Glycoprotein IIb; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit