2. Academic Validation
  3. p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521

p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521

  • Signal Transduct Target Ther. 2022 Aug 31;7(1):290. doi: 10.1038/s41392-022-01107-7.
Mingyang Ma  # 1 2,  Shuyao Hua  # 3,  Xiangde Min 4,  Liang Wang 4,  Jun Li 5,  Ping Wu 6,  Huifang Liang 2 7,  Bixiang Zhang 2 7 8 9 10,  Xiaoping Chen 11 12 13 14 15,  Shuai Xiang 16 17
Affiliations

Affiliations

  • 1 Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Clinical Nutrition, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 4 Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, China.
  • 6 Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Hubei Key Laboratory of Hepato-Pancreato-Biliary Disease, Wuhan, China.
  • 8 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
  • 9 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.
  • 10 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
  • 11 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 12 Hubei Key Laboratory of Hepato-Pancreato-Biliary Disease, Wuhan, China. [email protected].
  • 13 Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China. [email protected].
  • 14 Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China. [email protected].
  • 15 Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. [email protected].
  • 16 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 17 Hubei Key Laboratory of Hepato-Pancreato-Biliary Disease, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 36042225 DOI: 10.1038/s41392-022-01107-7
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.

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