F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway
The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80<sup>+</sup> KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver...
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MDPI AG
2021-04-01
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| author | Qingjun Lu Hao Shen Han Yu Jing Fu Hui Dong Yao Chen Hongyang Wang |
| author_facet | Qingjun Lu Hao Shen Han Yu Jing Fu Hui Dong Yao Chen Hongyang Wang |
| author_sort | Qingjun Lu |
| collection | DOAJ |
| description | The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80<sup>+</sup> KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80<sup>+</sup> KCs during the regenerative process. In RNA sequencing of isolated F4/80<sup>+</sup> KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80<sup>+</sup> KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80<sup>+</sup> KCs in the initiation and progression phases of liver regeneration. F4/80<sup>+</sup> KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80<sup>+</sup> KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80<sup>+</sup> KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake. |
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| last_indexed | 2024-03-10T12:23:42Z |
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| spelling | doaj.art-f1c6251a9983432c9b6a2da405b71ed92023-11-21T15:19:48ZengMDPI AGMolecules1420-30492021-04-01268223110.3390/molecules26082231F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 PathwayQingjun Lu0Hao Shen1Han Yu2Jing Fu3Hui Dong4Yao Chen5Hongyang Wang6State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, ChinaInternational Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, ChinaInternational Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, ChinaInternational Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, ChinaInternational Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, ChinaInternational Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, ChinaThe role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80<sup>+</sup> KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80<sup>+</sup> KCs during the regenerative process. In RNA sequencing of isolated F4/80<sup>+</sup> KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80<sup>+</sup> KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80<sup>+</sup> KCs in the initiation and progression phases of liver regeneration. F4/80<sup>+</sup> KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80<sup>+</sup> KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80<sup>+</sup> KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.https://www.mdpi.com/1420-3049/26/8/2231F4/80<sup>+</sup> Kupffer cellsliver regeneration2/3 hepatectomyOSMTGF-β2 |
| spellingShingle | Qingjun Lu Hao Shen Han Yu Jing Fu Hui Dong Yao Chen Hongyang Wang F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway Molecules F4/80<sup>+</sup> Kupffer cells liver regeneration 2/3 hepatectomy OSM TGF-β2 |
| title | F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway |
| title_full | F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway |
| title_fullStr | F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway |
| title_full_unstemmed | F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway |
| title_short | F4/80<sup>+</sup> Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway |
| title_sort | f4 80 sup sup kupffer cell derived oncostatin m sustains the progression phase of liver regeneration through inhibition of tgf β2 pathway |
| topic | F4/80<sup>+</sup> Kupffer cells liver regeneration 2/3 hepatectomy OSM TGF-β2 |
| url | https://www.mdpi.com/1420-3049/26/8/2231 |
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