The Role Of Myeloid PTEN In Liver Regeneration

Liver is an organ with remarkable regenerative capacity.Under normal physiological circumstances,hepatocytes are quiescent,but when liver is damaged,hepatocytes can re-enter the cell cycle and start a liver regeneration process.Liver regeneration is a complicated process,which is regulated by multiple factors.During this process liver macrophages play a critical role by releasing several cytokines which can stimulate hepatocytes to get rid of surveillance of checkpoint and to enter into cell cycle.Previous studies have shown that PTEN(Phosphatase and tensin homolog deleted on chromosome ten),an important tumor suppressor involved in cell proliferation and cell cycle progress,can negatively regulate multiple signaling pathways.The functions of PTEN are diverse in different cell types,and except its roles in cell proliferation and cell cycle,previous studies have proved that myeloid PTEN plays an important role in infection models,but its function in liver regeneration is still remained to be investigated.Our research aimed at studying the role of PTEN in myeloid cells during liver regeneration.We have already crossed Lys-Cre mice with PTENf/f mice to generate Lys-Cre;PTENf/f mice whose PTEN was specifically deficient in myeloid cells and established a 2/3 partial hepatectomy model.Our results obtained in this study are as follows:1.Myeloid PTEN deficient mice showed accelerated cell cycleProliferating cell nuclear antigen(PCNA)and Ki67 immunohistochemical stainings showed that PCNA-positive and Ki67-positive hepatocytes increased in myeloid PTEN specifically deficient Lys-Cre;PTENf/f mice,implying enhanced DNA synthesis and accelerated cell cycle progression.Liver mass restoration was another indicator of liver regeneration,our result showed that 10 days after 2/3 PHx,the ratio of liver weight to body weight increased significantly in Lys-Cre;PTENf/f mice,which meant faster liver mass restoration.2.Myeloid PTEN deficient mice showed enhanced Mitotic index after 2/3 partial hepatectomyMitotic index was a marker of proliferation level.Based on HE staining,we calculated the Mitotic index after 2/3 PHx,and found that Mitotic index in myeloid PTEN deficient mice was increased,which further suggested faster liver regeneration.3.Myeloid PTEN deficient mice showed similar liver injury compared with control miceAccording to liver pathology and serum ALT levels,we found that the liver injury of myeloid PTEN deficient mice was similar to control PTENf/f mice.And the mRNA levels of inflammatory cytokines such as TNF-a and IL-6 also similar in these two groups of mice.Furthermore,our in vitro studies discovered that BMDM from myeloid PTEN specifically deficient Lys-Cre;PTENf/f mice showed stronger tendency to M2 phenotypes than control PTENf/f mice in both cellular surface markers and mRNA levels,which in our speculation,may play a crucial role in liver regeneration.In conclusion,we demonstrated that during liver regeneration,myeloid PTEN deficiency promoted liver macrophage M2 polarization and liver cells proliferation,which consequently accelerate liver regeneration.