@article{2d8bf9496e064886b11def04ab4aa5fa,
title = "Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons",
abstract = "Direct conversion of human somatic fibroblasts into induced neurons (iNs) allows for the generation of functional neurons while bypassing any stem cell intermediary stages. Although iN technology has an enormous potential for modeling age-related diseases, as well as therapeutic approaches, the technology faces limitations due to variable conversion efficiencies and a lack of thorough understanding of the signaling pathways directing iN conversion. Here, we introduce a new all-in-one inducible lentiviral system that simplifies fibroblast transgenesis for the two pioneer transcription factors, Ngn2 and Ascl1, and markedly improves iN yields. Further, our timeline RNASeq data across the course of conversion has identified signaling pathways that become transcriptionally enriched during iN conversion. Small molecular modulators were identified for four signaling pathways that reliably increase the yield of iNs. Taken together, these advances provide an improved toolkit for iN technology and new insight into the mechanisms influencing direct iN conversion.",
author = "Joseph Herdy and Simon Schafer and Yongsung Kim and Zoya Ansari and Dina Zangwill and Manching Ku and Apua Paquola and Hyungjun Lee and Jerome Mertens and Gage, {Fred H.}",
note = "Funding Information: We thank the Coriell Institute, Johannes Schlachetzki and Jurgen Winkler at the University Hospital in Erlangen, and the Shiley-Marcos Alzheimer?s Disease Research Center at the University of California, San Diego (UCSD) for primary human fibroblasts, and Mary Lynn Gage for editorial comments. The study was supported by the Paul G. Allen Family Foundation, the National Institute on Aging (R01-AG056306-01 and K99-AG056679-01), the Austrian Science Fund FWF (SPIN doctoral school), the JPB Foundation, the Glenn Foundation Center for Aging Research, the American Federation for Aging Research (AFAR), the Leona M and Harry B Helmsley Charitable Trust (2012- PG-MED002), Annette Merle-Smith, CIRM (TR2-01778), The G Harold and Leila Y Mathers Charitable Foundation, and the 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. Funding Information: We thank the Coriell Institute, Johannes Schlachetzki and Jurgen Winkler at the University Hospital in Erlangen, and the Shiley-Marcos Alzheimer{\textquoteright}s Disease Research Center at the University of California, San Diego (UCSD) for primary human fibroblasts, and Mary Lynn Gage for editorial comments. The study was supported by the Paul G. Allen Family Foundation, the National Institute on Aging (R01-AG056306-01 and K99-AG056679-01), the Austrian Science Fund FWF (SPIN doctoral school), the JPB Foundation, the Glenn Foundation Center for Aging Research, the American Federation for Aging Research (AFAR), the Leona M and Harry B Helmsley Charitable Trust (2012-PG-MED002), Annette Merle-Smith, CIRM (TR2-01778), The G Harold and Leila Y Mathers Charitable Foundation, and the 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. Publisher Copyright: {\textcopyright} Herdy et al.",
year = "2019",
month = may,
doi = "10.7554/eLife.41356",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}