Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep

Edward Srour, Esmail D. Zanjani, Kenneth Cornetta, Christie Orschell, Alan W. Flake, Mark Hedrick, John E. Brandt, Tom Leemhuis, Ronald Hoffman

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3333-3342
Number of pages10
JournalBlood
Volume82
Issue number11
StatePublished - Dec 1 1993

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Stem cells
Sheep
Bone
Stem Cells
HLA-DR Antigens
Cells
Hematopoietic Stem Cells
T-cells
Bone Marrow
Animals
Bone Marrow Cells
Hematopoiesis
Grafts
Blood
Immunoglobulin G
T-Lymphocytes
Chimerism
Stem Cell Transplantation
Cell Lineage
Natural Killer Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep. / Srour, Edward; Zanjani, Esmail D.; Cornetta, Kenneth; Orschell, Christie; Flake, Alan W.; Hedrick, Mark; Brandt, John E.; Leemhuis, Tom; Hoffman, Ronald.

In: Blood, Vol. 82, No. 11, 01.12.1993, p. 3333-3342.

Research output: Contribution to journalArticle

Srour, E, Zanjani, ED, Cornetta, K, Orschell, C, Flake, AW, Hedrick, M, Brandt, JE, Leemhuis, T & Hoffman, R 1993, 'Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep', Blood, vol. 82, no. 11, pp. 3333-3342.
Srour, Edward ; Zanjani, Esmail D. ; Cornetta, Kenneth ; Orschell, Christie ; Flake, Alan W. ; Hedrick, Mark ; Brandt, John E. ; Leemhuis, Tom ; Hoffman, Ronald. / Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep. In: Blood. 1993 ; Vol. 82, No. 11. pp. 3333-3342.
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