Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors Journal Article
| Authors: | Chambers, S. M.; Qi, Y.; Mica, Y.; Lee, G.; Zhang, X. J.; Niu, L.; Bilsland, J.; Cao, L.; Stevens, E.; Whiting, P.; Shi, S. H.; Studer, L. |
| Article Title: | Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors |
| Abstract: | Considerable progress has been made in identifying signaling pathways that direct the differentiation of human pluripotent stem cells (hPSCs) into specialized cell types, including neurons. However, differentiation of hPSCs with extrinsic factors is a slow, step-wise process, mimicking the protracted timing of human development. Using a small-molecule screen, we identified a combination of five small-molecule pathway inhibitors that yield hPSC-derived neurons at >75% efficiency within 10 d of differentiation. The resulting neurons express canonical markers and functional properties of human nociceptors, including tetrodotoxin (TTX)-resistant, SCN10A-dependent sodium currents and response to nociceptive stimuli such as ATP and capsaicin. Neuronal fate acquisition occurs about threefold faster than during in vivo development, suggesting that use of small-molecule pathway inhibitors could become a general strategy for accelerating developmental timing in vitro. The quick and high-efficiency derivation of nociceptors offers unprecedented access to this medically relevant cell type for studies of human pain. © 2012 Nature America, Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; pyridines; pain; cell line; cell fate; cell differentiation; neurons; small molecule libraries; pyrimidines; cell type; gene expression regulation, developmental; molecular sequence data; nucleotide sequence; cell types; cell culture techniques; stem cells; in-vivo; pluripotent stem cell; pluripotent stem cells; adenosine triphosphate; pyrroles; in-vitro; sodium; nerve cell differentiation; small molecules; capsaicin; nociceptive receptor; nociceptors; signaling pathways; molecules; tetrodotoxin; caffeic acids; sodium current; human development; extrinsic factors; functional properties; pathway inhibitors; specialized cells; sodium channel nav1.8; nociceptive stimulation; acetanilides; nav1.8 voltage-gated sodium channel |
| Journal Title: | Nature Biotechnology |
| Volume: | 30 |
| Issue: | 7 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2012-07-01 |
| Start Page: | 715 |
| End Page: | 720 |
| Language: | English |
| DOI: | 10.1038/nbt.2249 |
| PROVIDER: | scopus |
| PUBMED: | 22750882 |
| PMCID: | PMC3516136 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2012" - "CODEN: NABIF" - "Source: Scopus" |
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