Nature Medicine
2, 1329 - 1337 (1996)
doi:10.1038/nm1296-1329
Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapyAndré Larochelle1, *, Josef Vormoor1, *, 4, Helmut Hanenberg2, Jean C.Y. Wang1, Mickie Bhatia1, Tsvee Lapidot1, 6, Thomas Moritz2, 5, Barbara Murdoch1, Xiang Li Xiao2, Ikunoshin Kato3, David A. WIlliams2
& John E. Dick1, 7
1Department of Genetics, Research Institute, Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
2Herman Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, and Howard Hughes Medical Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202-5225, USA
3Biotechnology Research Laboratories, Takara Shuzo Co. Ltd., Seta 3-4-1, Otsu, Shiga, 520-21, Japan
4J.V present address: Department of Paediatric Haematology/Oncology, University of Muenster, 48129 Muenster, Germany
5T.M. present address: Department of Internal Medicine (Tumorklinik), University of Essen, 45122 Essen, Germany
6T.L. present address: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel 76100
*These authors contributed equally to this work.
7Correspondence should be addressed to J.E.D. The development of stem−cell gene therapy is hindered by the absence of repopulation assays for primitive human hematopoietic cells. Current methods of gene transfer rely on in vitro colony−forming cell (CFC) and long−term culture−initiating cell (LTC−IC) assays, as well as inference from other mammalian species. We have identified a novel human hematopoietic cell, the SCID−repopulating cell (SRC), a cell more primitive than most LTC−ICs and CFCs. The SRC, exclusively present in the CD4+ CD8- fraction, is capable of multilineage repopulation of the bone marrow of nonobese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice). SRCs were rarely transduced with retroviruses, distinguishing them from most CFCs and LTC−ICs. This observation is consistent with the low level of gene marking seen in human gene therapy trials. An SRC assay may aid in the characterization of hematopoiesis, as well as the improvement of transduction methods.
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