1. CD105 is a surface marker for receptor-targeted gene transfer into human long-term repopulating hematopoietic stem cells.
- Author
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Kays SK, Kaufmann KB, Abel T, Brendel C, Bonig H, Grez M, Buchholz CJ, and Kneissl S
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD34 genetics, Antigens, CD34 metabolism, Cell Differentiation, Endoglin, Gene Targeting, Hematopoietic Stem Cells cytology, Humans, Interleukin Receptor Common gamma Subunit genetics, Interleukin Receptor Common gamma Subunit metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Receptors, Cell Surface genetics, Antigens, CD metabolism, Hematopoietic Stem Cells metabolism, Receptors, Cell Surface metabolism, Stem Cell Transplantation methods
- Abstract
Hematopoietic stem cells (HSCs) are an important target cell population for gene therapy since they can reconstitute the entire hematopoietic system. HSC-enriched cell populations can be recognized based on cell surface marker expression, such as CD34, which is broadly expressed on immature and partially differentiated cells. In mice, co-expression of CD34 and CD105 was previously shown to be relatively more specific for the most immature, long-term repopulating HSCs. Here, we evaluated whether CD105, which is expressed on 30%-80% of CD34(+) cells, is a marker also for human long-term repopulating HSCs. Therefore, we tracked the mature progeny of CD34(+) cells transduced with the CD105-targeted lentiviral vector CD105-LV in xenotolerant mice. Transduction was blocked with soluble CD105 protein confirming specificity. Importantly, CD105-LV transduced human CD34(+) cells engrafted in NOD-scid IL2Rγ(-/-) mice with up to 20% reporter gene-positive cells detected long term in all human hematopoietic lineages in bone marrow (BM), spleen, and blood. In addition, competitive repopulation experiments in mice showed a superior engraftment of CD105-LV transduced CD34(+) cells in BM and spleen compared with cells transduced with a conventional nontargeted lentiviral vector. Thus, human CD34(+)/CD105(+) cells are enriched for early HSCs with high repopulating capacity. Targeting this cell population with CD105-LV offers a novel gene transfer strategy to reach high engraftment rates of transduced cells and highlights the applicability of receptor-targeted vectors to trace cell subsets offering an alternative to prospective isolation by surface markers.
- Published
- 2015
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