title: CD105 is a surface marker for receptor-targeted gene transfer into human long-term repopulating hematopoietic stem cells.
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.
authors.affiliation: 1 Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut , Langen, Germany .
authors.forename: Sarah-Katharina
authors.initials: SK
authors.lastname: Kays
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Kaufmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Abel
authors.forename: Christian
authors.initials: C
authors.lastname: Brendel
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Buchholz
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kneissl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D000071063:Endoglin; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; C064206:ENG protein, human; D000071063:Endoglin; D053631:Interleukin Receptor Common gamma Subunit; D011956:Receptors, Cell Surface