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Donor Marker Infidelity in Transgenic Hematopoietic Stem Cells

^a Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA;
^b Departments of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA;
^c Department of Pediatrics, Emory University, Atlanta, Georgia, USA

Key Words. Hematopoietic stem cells • EGFP • Transgenic mouse • Bone marrow transplantation • Hematopoiesis

Correspondence: William H. Fleming, M.D., Ph.D., Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University (UHN73C), 3181 SW Sam Jackson Park Rd., Eugene, OR 97239 USA. Telephone: 503-494-1554; Fax: 503-494-2770; e-mail: flemingw{at}ohsu.edu

Transgenic marking approaches are increasingly used to evaluate the developmental potential of stem cells. However, cell fate mapping studies using different transgenic marking systems have produced conflicting results. These disparate findings may be due in part to the infidelity of donor marker gene expression. Analysis of hematopoietic stem cells (c-Kit⁺, Sca-1⁺, lineage marker^– [KSL]) from a transgenic mouse (1Osb) engineered to ubiquitously express the enhanced green fluorescent protein (EGFP) reveals two distinct populations. Forty percent of KSL cells demonstrate intermediate levels of EGFP fluorescence and differentiate into subpopulations of B cells, T cells, and myeloid cells that do not express EGFP. By contrast, progeny of the remaining 60% of KSL cells are almost exclusively EGFP bright. Long-term multilineage hematopoietic reconstitution and serial transplantation experiments show that these differences in EGFP are a property of self-renewing stem cells. Furthermore, both the transgene integration site and the activation status of a cell are important determinants of EGFP expression. These results indicate that a combination of donor cell markers is required to reliably track the full differentiation potential of transgenic stem cells.

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