Reprogramming Committed Murine Blood Cells to Induced Hematopoietic Stem Cells with Defined Factors

• Six defined factors impart HSC potential onto committed blood cells
• Adding Mycn and Meis1 and polycistronic viruses improves reprogramming efficacy
• Induced-HSCs possess differentiation and self-renewal potential at clonal level
• Transcriptional properties of induced-HSCs recapitulate true HSCs at clonal level

SummaryHematopoietic 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.

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