Kit Regulates HSC Engraftment across the Human-Mouse Species Barrier

• Published in: Cell stem cell 2014-08, Vol.15 (2), p.227-238
• Main Authors: Cosgun, Kadriye Nehir, Rahmig, Susann, Mende, Nicole, Reinke, Sören, Hauber, Ilona, Schäfer, Carola, Petzold, Anke, Weisbach, Henry, Heidkamp, Gordon, Purbojo, Ariawan, Cesnjevar, Robert, Platz, Alexander, Bornhäuser, Martin, Schmitz, Marc, Dudziak, Diana, Hauber, Joachim, Kirberg, Jörg, Waskow, Claudia
• Format: Article
• Language: English
• Subjects: Animals; Cell Lineage; Crosses, Genetic; Enzyme-Linked Immunosorbent Assay; Fetal Blood - cytology; Gene Expression Regulation; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cells - cytology; Humans; Lymphocytes - cytology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; RNA, Messenger - metabolism; Species Specificity; Stem Cell Factor - metabolism; Thymocytes - cytology; Time Factors
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2014.06.001

In-depth analysis of the cellular and molecular mechanisms regulating human HSC function will require a surrogate host that supports robust maintenance of transplanted human HSCs in vivo, but the currently available options are problematic. Previously we showed that mutations in the Kit receptor enhance engraftment of transplanted HSCs in the mouse. To generate an improved model for human HSC transplantation and analysis, we developed immune-deficient mouse strains containing Kit mutations. We found that mutation of the Kit receptor enables robust, uniform, sustained, and serially transplantable engraftment of human HSCs in adult mice without a requirement for irradiation conditioning. Using this model, we also showed that differential KIT expression identifies two functionally distinct subpopulations of human HSCs. Thus, we have found that the capacity of this Kit mutation to open up stem cell niches across species barriers has significant potential and broad applicability in human HSC research. [Display omitted] •Human HSCs engraft efficiently into adult immune-deficient Kit mutant mice•Kit mutation enables human HSC engraftment without irradiation conditioning•Human HSCs show robust multilineage engraftment and self-renewal in mice•Differential Kit expression delineates two subpopulations in the human HSC pool Adult mice with loss-of-function Kit mutations undergo efficient and stable engraftment of human HSCs without irradiation conditioning, providing a broadly applicable model for the analysis of human HSC function.