Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep.
We have previously reported the ability of uncharacterized human bone marrow (BM) cells to engraft into preimmune fetal sheep, thereby creating sheep-human chimera suitable for in vivo examination of the properties of human hematopoietic stem cells (HSC). Adult human bone marrow CD34+ HLA-DR- cells have been extensively characterized in vitro and have been demonstrated to contain a number of primitive hematopoietic progenitor cells (PHPC). However, the capacity of such highly purified populations of human marrow CD34+ HLA-DR- cells to undergo in vivo self-renewal and multipotential lymphohematopoietic differentiation has not been previously demonstrated. To achieve that, human CD34+ HLA-DR- cells were transplanted in utero into immunoincompetent fetal sheep to investigate the BM-populating potential of these cells. Long-term chimerism, sustained human hematopoiesis, and expression of human cells belonging to all human blood cell lineages were demonstrated in two animals for more than 7 months' posttransplantation. Chimeric BM contained erythroid, granulocytic/monocytic, and megakaryocytic hematopoietic progenitor cells, as well as the primitive high proliferative potential colony-forming cell (HPP-CFC). Under a variety of in vitro experimental conditions, chimeric BM cells gave rise to human T cells expressing T-lymphocyte-specific markers, human natural killer (NK) cells, and human IgG-producing B cells. In vivo expansion and possibly self-renewal of transplanted PHPC was confirmed by the detection in chimeric BM 130 days' posttransplantation of CD34+ HLA-DR- cells, the phenotype of human cells constituting the stem-cell graft. These studies demonstrate not only the BM-populating capacity, multipotential differentiation, and most likely self-renewal capabilities of human CD34+ HLA-DR- cells, but also that this BM population contains human HSC. Furthermore, it appears that this animal model of xenogeneic stem-cell transplantation is extremely useful for in vivo examination of human hematopoiesis and the behavioral and functional characteristics of human HSC.
Srour
E F
EF
Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis 46202-5121.
Zanjani
E D
ED
Cornetta
K
K
Traycoff
C M
CM
Flake
A W
AW
Hedrick
M
M
Brandt
J E
JE
Leemhuis
T
T
Hoffman
R
R
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001483:Base Sequence; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002678:Chimera; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000502:physiology*; D008969:Molecular Sequence Data; D011247:Pregnancy; D012756:Sheep; D014183:Transplantation, Heterologous
D015703:Antigens, CD; D018952:Antigens, CD34; D006684:HLA-DR Antigens