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Cell Stem Cell. 2019 Jan 3;24(1):166-182.e13. doi: 10.1016/j.stem.2018.11.015. Epub 2018 Dec 20.

Identification of Embryonic Neural Plate Border Stem Cells and Their Generation by Direct Reprogramming from Adult Human Blood Cells.

Author information

1
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: marc.thier@hi-stem.de.
2
Stem Cell Engineering Group, Institute of Reconstructive Neurobiology, Universität Bonn Life and Brain Center and Hertie Foundation, Sigmund-Freud Strasse 25, 53105 Bonn, Germany.
3
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
4
Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
5
Stem Cell and Regenerative Medicine Group, Institute of Anatomy and Cell Biology, Julius-Maximilians-Universität Würzburg, Koellikerstrasse 6, 97070 Würzburg, Germany.
6
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Experimental Hematology, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
8
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
9
Institute of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany.
10
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology, and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
11
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Health Data Science Unit and Bioquant Center, Medical Faculty of Heidelberg University, 69120 Heidelberg, Germany.
12
Stem Cell Engineering Group, Institute of Reconstructive Neurobiology, Universität Bonn Life and Brain Center and Hertie Foundation, Sigmund-Freud Strasse 25, 53105 Bonn, Germany; Leopold-Franzens-University Innsbruck, Institute of Molecular Biology & CMBI, Department Genomics, Stem Cell Biology & Regenerative Medicine, 6020 Innsbruck, Austria.
13
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: a.trumpp@dkfz.de.

Abstract

We report the direct reprogramming of both adult human fibroblasts and blood cells into induced neural plate border stem cells (iNBSCs) by ectopic expression of four neural transcription factors. Self-renewing, clonal iNBSCs can be robustly expanded in defined media while retaining multilineage differentiation potential. They generate functional cell types of neural crest and CNS lineages and could be used to model a human pain syndrome via gene editing of SCN9A in iNBSCs. NBSCs can also be derived from human pluripotent stem cells and share functional and molecular features with NBSCs isolated from embryonic day 8.5 (E8.5) mouse neural folds. Single-cell RNA sequencing identified the anterior hindbrain as the origin of mouse NBSCs, with human iNBSCs sharing a similar regional identity. In summary, we identify embryonic NBSCs and report their generation by direct reprogramming in human, which may facilitate insights into neural development and provide a neural stem cell source for applications in regenerative medicine.

KEYWORDS:

CRISPR; NSC; direct conversion; iNSC; neural crest; neural plate border; neural progenitor; neural stem cells; regenerative medicine

PMID:
30581079
DOI:
10.1016/j.stem.2018.11.015

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