Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons
Abstract Direct cell reprogramming, also called transdifferentiation, is valuable for cell fate studies and regenerative medicine. Current approaches to transdifferentiation are usually achieved by directly targeting the nuclear functions, such as manipulating the lineage‐specific transcriptional fa...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202104682 |
| _version_ | 1811234679224795136 |
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| author | Zheng‐Quan He Yu‐Huan Li Gui‐Hai Feng Xue‐Wei Yuan Zong‐Bao Lu Min Dai Yan‐Ping Hu Ying Zhang Qi Zhou Wei Li |
| author_facet | Zheng‐Quan He Yu‐Huan Li Gui‐Hai Feng Xue‐Wei Yuan Zong‐Bao Lu Min Dai Yan‐Ping Hu Ying Zhang Qi Zhou Wei Li |
| author_sort | Zheng‐Quan He |
| collection | DOAJ |
| description | Abstract Direct cell reprogramming, also called transdifferentiation, is valuable for cell fate studies and regenerative medicine. Current approaches to transdifferentiation are usually achieved by directly targeting the nuclear functions, such as manipulating the lineage‐specific transcriptional factors, microRNAs, and epigenetic modifications. Here, a robust method to convert fibroblasts to neurons through targeting the cytoskeleton followed by exposure to lineage‐specification surroundings is reported. Treatment of human foreskin fibroblasts with a single molecule inhibitor of the actomyosin contraction, can disrupt the cytoskeleton, promote cell softening and nuclear export of YAP/TAZ, and induce a neuron‐like state. These neuron‐like cells can be further converted into mature neurons, while single‐cell RNA‐seq shows the homogeneity of these cells during the induction process. Finally, transcriptomic analysis shows that cytoskeletal disruption collapses the original lineage expression profile and evokes an intermediate state. These findings shed a light on the underestimated role of the cytoskeleton in maintaining cell identity and provide a paradigm for lineage conversion through the regulation of mechanical properties. |
| first_indexed | 2024-04-12T11:39:44Z |
| format | Article |
| id | doaj.art-6c37447b43274ca29ab084980b4d6bc6 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-12T11:39:44Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-6c37447b43274ca29ab084980b4d6bc62022-12-22T03:34:41ZengWileyAdvanced Science2198-38442022-05-01913n/an/a10.1002/advs.202104682Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into NeuronsZheng‐Quan He0Yu‐Huan Li1Gui‐Hai Feng2Xue‐Wei Yuan3Zong‐Bao Lu4Min Dai5Yan‐Ping Hu6Ying Zhang7Qi Zhou8Wei Li9State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaKey Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences Beijing 100101 ChinaAbstract Direct cell reprogramming, also called transdifferentiation, is valuable for cell fate studies and regenerative medicine. Current approaches to transdifferentiation are usually achieved by directly targeting the nuclear functions, such as manipulating the lineage‐specific transcriptional factors, microRNAs, and epigenetic modifications. Here, a robust method to convert fibroblasts to neurons through targeting the cytoskeleton followed by exposure to lineage‐specification surroundings is reported. Treatment of human foreskin fibroblasts with a single molecule inhibitor of the actomyosin contraction, can disrupt the cytoskeleton, promote cell softening and nuclear export of YAP/TAZ, and induce a neuron‐like state. These neuron‐like cells can be further converted into mature neurons, while single‐cell RNA‐seq shows the homogeneity of these cells during the induction process. Finally, transcriptomic analysis shows that cytoskeletal disruption collapses the original lineage expression profile and evokes an intermediate state. These findings shed a light on the underestimated role of the cytoskeleton in maintaining cell identity and provide a paradigm for lineage conversion through the regulation of mechanical properties.https://doi.org/10.1002/advs.202104682cytoskeletonlineage conversionmechanical modulationsmall molecules |
| spellingShingle | Zheng‐Quan He Yu‐Huan Li Gui‐Hai Feng Xue‐Wei Yuan Zong‐Bao Lu Min Dai Yan‐Ping Hu Ying Zhang Qi Zhou Wei Li Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons Advanced Science cytoskeleton lineage conversion mechanical modulation small molecules |
| title | Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons |
| title_full | Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons |
| title_fullStr | Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons |
| title_full_unstemmed | Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons |
| title_short | Pharmacological Perturbation of Mechanical Contractility Enables Robust Transdifferentiation of Human Fibroblasts into Neurons |
| title_sort | pharmacological perturbation of mechanical contractility enables robust transdifferentiation of human fibroblasts into neurons |
| topic | cytoskeleton lineage conversion mechanical modulation small molecules |
| url | https://doi.org/10.1002/advs.202104682 |
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