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Persistence of human multilineage, self-renewing lymphohematopoietic stem
cells in chimeric sheep
EF Srour, ED Zanjani, K Cornetta, CM Traycoff, AW Flake, M Hedrick, JE Brandt, T Leemhuis and R Hoffman
Division of Hematology/Oncology, Indiana University School of Medicine,
Indianapolis 46202-5121.
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.
Volume 82,
Issue 11,
pp. 3333-3342,
12/01/1993
Copyright © 1993 by The American Society of Hematology
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