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.
authors: Center for Stem Cell Biology, Sloan-Kettering Institute, New York, New York, USA. chambers@mskcc.org
authors: Stuart M
authors: SM
authors: Chambers
authors: Yuchen
authors: Y
authors: Qi
authors: Yvonne
authors: Y
authors: Mica
authors: Gabsang
authors: G
authors: Lee
authors: Xin-Jun
authors: XJ
authors: Zhang
authors: Lei
authors: L
authors: Niu
authors: James
authors: J
authors: Bilsland
authors: Lishuang
authors: L
authors: Cao
authors: Edward
authors: E
authors: Stevens
authors: Paul
authors: P
authors: Whiting
authors: Song-Hai
authors: SH
authors: Shi
authors: Lorenz
authors: L
authors: Studer
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D002109:Caffeic Acids; C473711:Chir 99021; C560455:N-(4-(3-(3,4-dihydroxyphenyl)acryloyl)phenyl)-2-(thiophen-2-yl)acetamide; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C568317:SCN10A protein, human; C105686:SU 5402; D054852:Small Molecule Libraries; D013779:Tetrodotoxin