Embryonic stem cell-derived hematopoietic stem cells.
Despite two decades of studies documenting the in vitro blood-forming potential of murine embryonic stem cells (ESCs), achieving stable long-term blood engraftment of ESC-derived hematopoietic stem cells in irradiated mice has proven difficult. We have exploited the Cdx-Hox pathway, a genetic program important for blood development, to enhance the differentiation of ESCs along the hematopoietic lineage. Using an embryonic stem cell line engineered with tetracycline-inducible Cdx4, we demonstrate that ectopic Cdx4 expression promotes hematopoietic mesoderm specification, increases hematopoietic progenitor formation, and, together with HoxB4, enhances multilineage hematopoietic engraftment of lethally irradiated adult mice. Clonal analysis of retroviral integration sites confirms a common stem cell origin of lymphoid and myeloid populations in engrafted primary and secondary mice. These data document the cardinal stem cell features of self-renewal and multilineage differentiation of ESC-derived hematopoietic stem cells.
Wang
Yuan
Y
Division of Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Division of Hematology, Brigham and Women's Hospital, Harvard Stem Cell Institute, Boston, MA 02115, USA.
Yates
Frank
F
Naveiras
Olaia
O
Ernst
Patricia
P
Daley
George Q
GQ
D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry; D015139:Blotting, Southern; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002469:Cell Separation; D017690:Cell Transplantation; D004247:DNA / Q000737:chemistry; D004622:Embryo, Mammalian / Q000166:cytology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D019076:Transgenes
D000954:Antigens, Surface; C084563:Cdx4 protein, mouse; D018398:Homeodomain Proteins; D004247:DNA