Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity
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 mu...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716316515 |
| _version_ | 1828526698668228608 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yi-Fen Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T21:27:41Z |
| format | Article |
| id | doaj.art-679c902f28b84dce9db31c4a72891793 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T21:27:41Z |
| publishDate | 2016-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-679c902f28b84dce9db31c4a728917932022-12-22T00:50:16ZengElsevierCell Reports2211-12472016-12-0117123178319210.1016/j.celrep.2016.11.077Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive ImmunityYi-Fen Lu0Patrick Cahan1Samantha Ross2Julie Sahalie3Patricia M. Sousa4Brandon K. Hadland5Wenqing Cai6Erik Serrao7Alan N. Engelman8Irwin D. Bernstein9George Q. Daley10Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAStem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 02115, USAHematopoietic 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.http://www.sciencedirect.com/science/article/pii/S2211124716316515hematopoietic stem cellHSC engineeringESC-HSCHoxB4Notchadaptive immunityadult globinlineage-priming |
| spellingShingle | 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 Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity Cell Reports hematopoietic stem cell HSC engineering ESC-HSC HoxB4 Notch adaptive immunity adult globin lineage-priming |
| title | Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity |
| title_full | Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity |
| title_fullStr | Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity |
| title_full_unstemmed | Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity |
| title_short | Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity |
| title_sort | engineered murine hscs reconstitute multi lineage hematopoiesis and adaptive immunity |
| topic | hematopoietic stem cell HSC engineering ESC-HSC HoxB4 Notch adaptive immunity adult globin lineage-priming |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716316515 |
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