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Cell Stem Cell. 2016 May 5;18(5):653-67. doi: 10.1016/j.stem.2016.03.020. Epub 2016 Apr 28.

Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation.

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
5
Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: sheng.ding@gladstone.ucsf.edu.

Abstract

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.

PMID:
27133794
PMCID:
PMC4864020
DOI:
10.1016/j.stem.2016.03.020
[Indexed for MEDLINE]
Free PMC Article

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