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Stem Cell Reports. 2017 Oct 10;9(4):1024-1033. doi: 10.1016/j.stemcr.2017.08.010. Epub 2017 Sep 21.

In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma.

Author information

1
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
2
Department of Pathology, Research Hospital, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
3
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
4
Project Division of Advanced Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
6
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Electronic address: nakauchi@ims.u-tokyo.ac.jp.
7
Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Project Division of Advanced Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: y-sato4@ims.u-tokyo.ac.jp.

Abstract

Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) could potentially provide unlimited HSCs for clinical transplantation, a curative treatment for numerous blood diseases. However, to date, bona fide HSC generation has been largely unsuccessful in vitro. We have previously described proof of concept for in vivo HSC generation from PSCs via teratoma formation. However, our first-generation system was complex and the output low. Here, we further optimize this technology and demonstrate the following: (1) simplified HSC generation using transcription factor overexpression; (2) improved HSC output using c-Kit-deficient host mice, and (3) that teratomas can be transplanted and cryopreserved. We demonstrate that overexpression of Gfi1b, c-Fos, and Gata2, previously reported to transdifferentiate fibroblasts into hematopoietic progenitors in vitro, can induce long-term HSC formation in vivo. Our in vivo system provides a useful platform to investigate new strategies and re-evaluate existing strategies to generate HSCs and study HSC development.

KEYWORDS:

Gata2; Gfi1b; cFos; hematopoietic stem cell; hemogenic endothelium; induced pluripotent stem cell; teratomas

PMID:
28943250
PMCID:
PMC5639260
DOI:
10.1016/j.stemcr.2017.08.010
[Indexed for MEDLINE]
Free PMC Article

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