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Cell Rep. 2016 Dec 20;17(12):3178-3192. doi: 10.1016/j.celrep.2016.11.077.

Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity.

Author information

1
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Biomedical Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
4
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
5
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA.
6
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
7
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: george.daley@childrens.harvard.edu.

Abstract

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.

KEYWORDS:

ESC-HSC; HSC engineering; HoxB4; Notch; adaptive immunity; adult globin; hematopoietic stem cell; lineage-priming

PMID:
28009288
PMCID:
PMC5247798
DOI:
10.1016/j.celrep.2016.11.077
[Indexed for MEDLINE]
Free PMC Article

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