p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521
Abstract Hepatic progenitor cells (HPCs) hold tremendous potential for liver regeneration, but their well-known limitation of proliferation hampers their broader use. There is evidence that laminin is required for the proliferation of HPCs, but the laminin isoform that plays the dominant role and th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01107-7 |
| _version_ | 1798004454138576896 |
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| author | Mingyang Ma Shuyao Hua Xiangde Min Liang Wang Jun Li Ping Wu Huifang Liang Bixiang Zhang Xiaoping Chen Shuai Xiang |
| author_facet | Mingyang Ma Shuyao Hua Xiangde Min Liang Wang Jun Li Ping Wu Huifang Liang Bixiang Zhang Xiaoping Chen Shuai Xiang |
| author_sort | Mingyang Ma |
| collection | DOAJ |
| description | Abstract Hepatic progenitor cells (HPCs) hold tremendous potential for liver regeneration, but their well-known limitation of proliferation hampers their broader use. There is evidence that laminin is required for the proliferation of HPCs, but the laminin isoform that plays the dominant role and the key intracellular downstream targets that mediate the regulation of HPC proliferation have yet to be determined. Here we showed that p53 expression increased gradually and reached maximal levels around 8 days when laminin α4, α5, β2, β1, and γ1 subunit levels also reached a maximum during HPC activation and expansion. Laminin-521 (LN-521) promoted greater proliferation of HPCs than do laminin, matrigel or other laminin isoforms. Inactivation of p53 by PFT-α or Ad-p53V143A inhibited the promotion of proliferation by LN-521. Further complementary MRI and bioluminescence imaging analysis showed that p53 inactivation decreased the proliferation of transplanted HPCs in vivo. p53 was activated by LN-521 through the Integrin α6β1/FAK-Src-Paxillin/Akt axis. Activated p53 was involved in the nuclear translocation of CDK4 and inactivation of Rb by inducing p27Kip1. Taken together, this study identifies LN-521 as an ideal candidate substrate for HPC culture and uncovers an unexpected positive role for p53 in regulating proliferation of HPCs, which makes it a potential target for HPC-based regenerative medicine. |
| first_indexed | 2024-04-11T12:24:03Z |
| format | Article |
| id | doaj.art-bcec34f2e316478d8d4c0b6c9f86eacd |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-11T12:24:03Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-bcec34f2e316478d8d4c0b6c9f86eacd2022-12-22T04:24:00ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352022-08-017111710.1038/s41392-022-01107-7p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521Mingyang Ma0Shuyao Hua1Xiangde Min2Liang Wang3Jun Li4Ping Wu5Huifang Liang6Bixiang Zhang7Xiaoping Chen8Shuai Xiang9Department of General Surgery, Tianjin Medical University General HospitalDepartment of Clinical Nutrition, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis ControlDepartment of Pathophysiology, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Hepatic progenitor cells (HPCs) hold tremendous potential for liver regeneration, but their well-known limitation of proliferation hampers their broader use. There is evidence that laminin is required for the proliferation of HPCs, but the laminin isoform that plays the dominant role and the key intracellular downstream targets that mediate the regulation of HPC proliferation have yet to be determined. Here we showed that p53 expression increased gradually and reached maximal levels around 8 days when laminin α4, α5, β2, β1, and γ1 subunit levels also reached a maximum during HPC activation and expansion. Laminin-521 (LN-521) promoted greater proliferation of HPCs than do laminin, matrigel or other laminin isoforms. Inactivation of p53 by PFT-α or Ad-p53V143A inhibited the promotion of proliferation by LN-521. Further complementary MRI and bioluminescence imaging analysis showed that p53 inactivation decreased the proliferation of transplanted HPCs in vivo. p53 was activated by LN-521 through the Integrin α6β1/FAK-Src-Paxillin/Akt axis. Activated p53 was involved in the nuclear translocation of CDK4 and inactivation of Rb by inducing p27Kip1. Taken together, this study identifies LN-521 as an ideal candidate substrate for HPC culture and uncovers an unexpected positive role for p53 in regulating proliferation of HPCs, which makes it a potential target for HPC-based regenerative medicine.https://doi.org/10.1038/s41392-022-01107-7 |
| spellingShingle | Mingyang Ma Shuyao Hua Xiangde Min Liang Wang Jun Li Ping Wu Huifang Liang Bixiang Zhang Xiaoping Chen Shuai Xiang p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 Signal Transduction and Targeted Therapy |
| title | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 |
| title_full | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 |
| title_fullStr | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 |
| title_full_unstemmed | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 |
| title_short | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521 |
| title_sort | p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin 521 |
| url | https://doi.org/10.1038/s41392-022-01107-7 |
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