Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity
Yi-Fen Lu,
Patrick Cahan,
Samantha Ross,
Julie Sahalie,
Patricia M. Sousa,
Brandon K. Hadland,
Wenqing Cai,
Erik Serrao,
Alan N. Engelman,
Irwin D. Bernstein,
George Q. Daley
Affiliations
Yi-Fen Lu
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Patrick Cahan
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Samantha Ross
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Julie Sahalie
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Patricia M. Sousa
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Brandon K. Hadland
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Wenqing Cai
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Erik Serrao
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Alan N. Engelman
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Irwin D. Bernstein
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
George Q. Daley
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USA
Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming.
