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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0407.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2737-2743
HEMATOPOIESIS
Polyclonal long-term repopulating stem cell clones in a
primate model
Manfred Schmidt,
Philipp Zickler,
Gesa Hoffmann,
Sebastian Haas,
Manuela Wissler,
Arne Muessig,
John F. Tisdale,
Ken Kuramoto,
Robert G. Andrews,
Tong Wu,
Hans-Peter Kiem,
Cynthia E. Dunbar, and
Christof von
Kalle
From Department I of Internal Medicine and the
Institute for Molecular Medicine and Cell Research, University of
Freiburg, Germany; the Molecular and Clinical Hematology Branch,
National Institute of Diabetes and Digestive and Kidney Disorders, and
the Hematology Branch, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD; and the Clinical Research
Division, Fred Hutchinson Cancer Research Center, the Washington
Regional Primate Research Center, University of Washington, and the
Departments of Pediatrics and Medicine, University of Washington School
of Medicine, Seattle, WA.
Hematopoietic bone marrow stem cells generate differentiated blood
cells and, when transplanted, may contribute to other organs, such as
the brain, heart, and liver. An understanding of in vivo clonal
behavior of stem cells will have important implications for cellular
and gene therapy. For the first time, we have directly demonstrated the
derivation of circulating peripheral blood cells from individual stem
cell clones. We analyzed the clonal composition of retrovirus-marked
peripheral blood leukocyte populations in 2 different primate models by
a novel direct genomic sequencing technique allowing the identification
of vector insertion sites. More than 80 contributing long-term
hematopoietic clones were identified in individual rhesus macaque
peripheral blood transplant recipients and more than 25 different clones in a baboon marrow transplant recipient. Up to 5 insertion sequences from each animal were used to trace the long-term
contribution of stem cell clones in these primate models. Continuous
and mostly pluripotent contributions of peripheral blood leukocytes
from each of the traced clones could be detected for the entire
follow-up period of 23 to 33 months. Our study provides direct
molecular evidence for a polyclonal, multilineage, and sustained
contribution of individual stem cells to primate hematopoiesis.
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