Modulation of liver regeneration via myeloid PTEN deficiency

Abstract

Molecular mechanisms that modulate liver regeneration are of critical importance for a number of hepatic disorders. Kupffer cells and natural killer (NK) cells are two cell subsets indispensable for liver regeneration. We have focused on these two populations and, in particular, the interplay between them. Importantly, we demonstrate that deletion of the myeloid phosphatase and tensin homolog on chromosome 10 (PTEN) leading to an M2-like polarization of Kupffer cells, which results in decreased activation of NK cells. In addition, PTEN-deficient Kupffer cells secrete additional factors that facilitate the proliferation of hepatocytes. In conclusion, PTEN is critical for inhibiting M2-like polarization of Kupffer cells after partial hepatectomy, resulting in NK cell activation and thus the inhibition of liver regeneration. Furthermore, PTEN reduces growth factor secretion by Kupffer cells. Our results suggest that targeting PTEN on Kupffer cells may be useful in altering liver regeneration in patients undergoing liver resection.

C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a–dependent manner

“…[ 11 , 12 ] For instance, phosphatase and tensin homologue deleted on chromosome 10, 10q23.3 KO in macrophages has been reported to promote reparative macrophage polarization and exert proregenerative effects after 70% PHx. [ 29 ] In addition, LR and recovery of liver function are accelerated significantly when reparative bone‐marrow–derived macrophages (BMDMs) are infused into hepatectomized mice. [ 13 ] However, the underlying mechanism in which reparative macrophages affected LR were not clearly shown.…”

Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells

“…Therefore, scientists have researched the interplay between them in the hope of better outcomes for chronic liver diseases. Ma et al 110 demonstrated that the deletion of phosphatase and tensin homolog (PTEN), originally identified as a tumor-suppressor protein, could activate the M2 polarization of Kupffer cells, leading to the less activated phenotype of NK cells, probably through direct cell-cell contact or decreased secretion levels of IL12 and IL15. Furthermore, PTEN-deficient Kupffer cells secreted more growth factors required for liver regeneration, 110 identifying PTEN as a potential target for liver regeneration.…”

“…Ma et al 110 demonstrated that the deletion of phosphatase and tensin homolog (PTEN), originally identified as a tumor-suppressor protein, could activate the M2 polarization of Kupffer cells, leading to the less activated phenotype of NK cells, probably through direct cell-cell contact or decreased secretion levels of IL12 and IL15. Furthermore, PTEN-deficient Kupffer cells secreted more growth factors required for liver regeneration, 110 identifying PTEN as a potential target for liver regeneration. For NK cells, they have been previously proved to be beneficial for attenuating inflammation and preventing adverse cardiac remodeling via the cell crosstalk with allogeneic human cardiac-derived progenitor cells, 111 implying their potential roles in LPLC-induced liver regeneration.…”

PTEN-mediated AKT/β-catenin signaling enhances the proliferation and expansion of Lgr5+ hepatocytes

“…PTEN-mediated AKT/β-catenin signaling controls inflammatory damage in mouse liver triggered by ischemia/reperfusion injury and regulates the release of inflammatory cytokines in the liver 31 . Meanwhile, PTEN regulates NK cells and Kupffer cells in the liver to modulate the proliferation of hepatocytes to promote liver repair 32 . However, the role of PTEN in Lgr5+ hepatocytes mediated liver regeneration remains to be explored.…”