Abstract
Scientific and technological advances of the past decade have shed light on the mechanisms underlying cell fate acquisition, including its transcriptional and epigenetic regulation during embryonic development. This knowledge has enabled us to purposefully engineer cell fates in vitro by manipulating expression levels of lineage-instructing transcription factors. Here, we review the state of the art in the cell programming field with a focus on the derivation of neural cells. We reflect on what we know about the mechanisms underlying fate changes in general and on the degree of epigenetic remodeling conveyed by the distinct reprogramming and direct conversion strategies available. Moreover, we discuss the implications of residual epigenetic memory for biomedical applications such as disease modeling and neuroregeneration. Finally, we cover recent developments approaching cell fate conversion in the living brain and define questions which need to be addressed before cell programming can become an integral part of translational medicine.
Highlights
Scientific and technological advances of the past decade have shed light on the mechanisms underlying cell fate acquisition, including its transcriptional and epigenetic regulation during embryonic development
This changed dramatically when Kazutoshi Takahashi and Shinya Yamanaka revealed that overexpression of the four transcription factor (TF) Oct3/4, Sox2, Klf4, and avian myelocytomatosis viral oncogene cellular homolog (c-Myc) is sufficient to induce a pluripotent state in mouse3 and human4 fibroblasts
An exemplar for such a “partial” reprogramming is the Oct3/4, Sox2, Klf4, and c-Myc-driven derivation of neural stem cells (NSCs) from fibroblasts6–10 or blood cells11, where transgene expression was combined with an exposure to FGF2, FGF4, and/or EGF6,7,10,11, FGF2 and/or epidermal growth factor (EGF) in conjunction with LIF8, or LIF in combination with the TGFβ-inhibitor SB431542 and the GSK3β-inhibitor CHIR990219
Summary
Brn, Myt1l Ascl, Brn and Myt1l or Ascl, Brn, Ngn None (chemical reprogramming) Several (CRISPR activation screen) Several (TF screen) Ascl, Brn, Myt1l miR124, BRN2, MYT1L ASCL1, BRN2, MYT1L, NEUROD1 ASCL1, BRN2, MYT1L miR9/9* and miR124 (+ ASCL1, MYT1L and/or NEUROD2) ASCL1, NGN2 miR-124 regulated ASCL1, BRN2, MYT1L ASCL1, BRN2, MYT1L shp and/or shp or hTERT ASCL1, NGN2 (Ladewig et al (2012)52) miR9/9*, miR124 (Yoo et al (2011)51) ASCL1, BRN2, MYT1L (Pereira et al (2014)47) NGN2 ASCL1, BRN2 (+ shRNA REST) ASCL1, NGN2 (Mertens et al (2015)56) ASCL1, NGN2 Neurod Ascl None (chemical reprogramming) BRN2, MYT1L, FEZF2 None (chemical reprogramming). Li et al (2015)47 Liu et al (2018)48 Tsunemoto et al (2018)49 Torper et al (2013)50 Ambasudhan et al (2011)19 Pang et al (2011) Pfisterer et al (2011)17 Yoo et al (2011). Smith et al (2016)59 Drouin-Ouellet et al (2017)60 Kim et al (2018)61 Herdy et al (2019)62 Matsuda et al (2019)35 Chanda et al (2014)63 Hu et al (2015)64 Miskinyte et al (2017)65 Park et al (2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
