Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening
Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the result...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/135676 |
| _version_ | 1811069580234194944 |
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| author | Khan, Shafqat A Park, Kyoung-mi Fischer, Laura A Dong, Chen Lungjangwa, Tenzin Jimenez, Marta Casalena, Dominick Chew, Brian Dietmann, Sabine Auld, Douglas S Jaenisch, Rudolf Theunissen, Thorold W |
| author_facet | Khan, Shafqat A Park, Kyoung-mi Fischer, Laura A Dong, Chen Lungjangwa, Tenzin Jimenez, Marta Casalena, Dominick Chew, Brian Dietmann, Sabine Auld, Douglas S Jaenisch, Rudolf Theunissen, Thorold W |
| author_sort | Khan, Shafqat A |
| collection | MIT |
| description | Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ∼3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naive resetting in combination with PKC, ROCK, and TNKS inhibitors and activin A. This work demonstrates that induction and maintenance of naive human pluripotency are governed by distinct signaling requirements. |
| first_indexed | 2024-09-23T08:12:36Z |
| format | Article |
| id | mit-1721.1/135676 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:12:36Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1356762021-10-28T05:01:08Z Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening Khan, Shafqat A Park, Kyoung-mi Fischer, Laura A Dong, Chen Lungjangwa, Tenzin Jimenez, Marta Casalena, Dominick Chew, Brian Dietmann, Sabine Auld, Douglas S Jaenisch, Rudolf Theunissen, Thorold W Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ∼3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naive resetting in combination with PKC, ROCK, and TNKS inhibitors and activin A. This work demonstrates that induction and maintenance of naive human pluripotency are governed by distinct signaling requirements. 2021-10-27T20:24:34Z 2021-10-27T20:24:34Z 2021 2021-07-19T16:32:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135676 en 10.1016/j.celrep.2021.109233 Cell Reports Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Khan, Shafqat A Park, Kyoung-mi Fischer, Laura A Dong, Chen Lungjangwa, Tenzin Jimenez, Marta Casalena, Dominick Chew, Brian Dietmann, Sabine Auld, Douglas S Jaenisch, Rudolf Theunissen, Thorold W Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title | Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title_full | Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title_fullStr | Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title_full_unstemmed | Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title_short | Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening |
| title_sort | probing the signaling requirements for naive human pluripotency by high throughput chemical screening |
| url | https://hdl.handle.net/1721.1/135676 |
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