HEMATOPOIETIC DEFECTS IN MICE LACKING THE SIALOMUCIN CD34

Although the pluripotent hematopoietic stem cell can only be definitiv ely identified by its ability to reconstitute the various mature blood lineages, a diversity of cell surface antigens have also been specifi cally recognized on this subset of hematopoietic progenitors. One such stem cell-associated antigen is the sialomucin CD34, a highly O-glyco sylated cell surface glycoprotein that has also been shown to be expre ssed on all vascular endothelial cells throughout murine embryogenesis as well as in the adult. The functional significance of CD34 expressi on on hematopoietic progenitor cells and developing blood vessels is u nknown. To analyze the involvement of CD34 in hematopoiesis, we have p roduced both embryonic stem (ES) cells and mice that are null for the expression of this mucin. Analysis of yolk sac-like hematopoietic deve lopment in embryoid bodies derived from CD34-null ES cells showed a si gnificant delay in both erythroid and myeloid differentiation that cou ld be reversed by transfection of the mutant ES cells with CD34 constr ucts expressing either a complete or truncated cytoplasmic domain. Mea surements of colony-forming activity of hematopoietic progenitor cells derived from yolk sacs or fetal livers isolated from CD34-null embryo s also showed a decreased number of these precursor cells. In spite of these diminished embryonic hematopoietic progenitor numbers, the CD34 -null mice developed normally, and the hematopoietic profile of adult blood appeared typical. However, the colony-forming activity of hemato poietic progenitors derived from both bone marrow and spleen is signif icantly reduced in adult CD34-deficient animals, and these CD34-defici ent progenitors also appear to be unable to expand in liquid cultures in response to hematopoietic growth factors. Even with these apparent progenitor cell deficiencies, CD34-null animals showed kinetics of ery throid, myeloid, and platelet recovery after sublethal irradiation tha t are indistinguishable from wild-type mice. These data strongly sugge st that CD34 plays an important role in the formation of progenitor ce lls during both embryonic and adult hematopoiesis. However, the hemato poietic sites of adult CD34-deficient mice may still have a significan t reservoir of progenitor cells that allows for normal recovery after nonmyeloablative peripheral cell depletion. (C) 1996 by The American S ociety of Hematology.