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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0407.
Submitted February 7, 2002
Accepted May 22, 2002
Polyclonal long-term repopulating stem cell clones in a primate model
Manfred Schmidt, Philipp Zickler, Gesa Hoffman, Sebastian Haas, Manuela Wissler, Arne Muessig, John F Tisdale, Robert G Andrews, Tong Wu, Hans-Peter Kiem, Cynthia E Dunbar*, and Christof von Kalle
Department of Internal Medicine, University of Freiburg, Freiburg, Germany
Department of Internal Medicine, University of Freiburg, Freiburg, Germany; National Heart, Lung & Blood Institute, National Institutes of Health, Bethesda, MD, USA
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Washington Regional Primate Research Center, University of Washington, Seattle, WA, USA; Departments of Pediatrics and Medicine, University of Washington School of Medicine, Seattle, WA, USA
Hematology Branch, National Heart, Lung & Blood Institute, National Institutes of Health, Bethesda, MD, USA
Department of Internal Medicine, University of Freiburg, Freiburg, Germany; Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
* Corresponding author; email: cedunbar{at}erols.com.
Hematopoietic bone marrow stem cells generate differentiated blood cells and, when transplanted, may contribute to other organs such as 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 two different primate models by a novel direct genomic sequencing technique allowing the identification of vector insertion sites. Over 80 contributing long-term hematopoietic clones were identified in individual rhesus macaque peripheral blood transplantation recipients and over 25 different clones in a baboon marrow transplantation 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 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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