Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors.
Hematopoietic stem cells (HSCs) sustain blood formation throughout life and are the functional units of bone marrow transplantation. We show that transient expression of six transcription factors Run1t1, Hlf, Lmo2, Prdm5, Pbx1, and Zfp37 imparts multilineage transplantation potential onto otherwise committed lymphoid and myeloid progenitors and myeloid effector cells. Inclusion of Mycn and Meis1 and use of polycistronic viruses increase reprogramming efficacy. The reprogrammed cells, designated induced-HSCs (iHSCs), possess clonal multilineage differentiation potential, reconstitute stem/progenitor compartments, and are serially transplantable. Single-cell analysis revealed that iHSCs derived under optimal conditions exhibit a gene expression profile that is highly similar to endogenous HSCs. These findings demonstrate that expression of a set of defined factors is sufficient to activate the gene networks governing HSC functional identity in committed blood cells. Our results raise the prospect that blood cell reprogramming may be a strategy for derivation of transplantable stem cells for clinical application.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Jonah
J
Riddell
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Roi
R
Gazit
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Brian S
BS
Garrison
Dana Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Boston, MA 02116, USA.
Guoji
G
Guo
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
Assieh
A
Saadatpour
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Pankaj K
PK
Mandal
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Wataru
W
Ebina
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA.
Pavel
P
Volchkov
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
Guo-Cheng
GC
Yuan
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Dana Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Boston, MA 02116, USA; Howard Hughes Medical Institute; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Stuart H
SH
Orkin
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: derrick.rossi@childrens.harvard.edu.
Derrick J
DJ
Rossi
D000818:Animals; D065150:Cellular Reprogramming; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome
D018398:Homeodomain Proteins; C571825:MYCN protein, mouse; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors