Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • br Acknowledgments br Introduction Liver disease

    2021-10-11


    Acknowledgments
    Introduction Liver disease is one of the leading causes of death worldwide. Death from any type of acute or chronic liver injury results when sufficient healthy hepatic parenchyma cannot be regenerated to perform vital liver-specific functions. Although the regenerative capability of adult liver is fabled, 10–20% of individuals exhibit defective regenerative responses that progressively replace functional liver tissue with scar tissue, placing them at risk of cirrhosis and primary liver cancer when confronted with chronic liver injury. The prognosis of cirrhosis is worse than that of many malignancies given that survival is merely two to four years once evidence of liver dysfunction becomes overt. Further, after cirrhosis has developed, reversing it is an extremely difficult and lengthy process, even after eliminating the underlying cause of liver injury. These dismal statistics underscore the importance of developing effective strategies to prevent and treat cirrhosis. Cirrhosis is an extreme consequence of recurrent futile efforts to repair liver injury. The liver has robust regenerative capability and typically responds to injury with precisely-coordinated wound healing responses that persist until healthy hepatic parenchyma is completely restored. Injured liver epithelial Pseudo-UTP trigger wound healing by releasing signals that mobilise various types of cells that must collaborate to reconstruct healthy hepatic parenchyma. Immune cells are recruited to combat invading pathogens, remove dying epithelial cells, and help activate resident hepatic stellate cells (HSCs) and sinusoidal endothelial cells. In turn, these sinusoidal cells generate signals that stimulate vasculogenesis and matrix remodelling. Together with epithelial and immune cell-derived factors, the changes in blood flow and matrix composition promote the viability of surviving epithelial cells while nurturing the outgrowth and eventual differentiation of progenitors needed to repopulate the damaged parenchyma. During these wound-healing responses the accumulation of immune cells, activated endothelial cells, myofibroblasts, and progenitors, as well as the resultant matrix and vascular remodelling (a.k.a. scarring) disrupt the normal hepatic architecture. However, as healthy hepatic parenchyma is regenerated, the signals driving repair dissipate, wound healing responses subside, and scarring gradually regresses. Wound healing “stalls” during the phase of active scarring when liver injury is recurrent or when the mechanisms that orchestrate the wound healing process become dysregulated. In order to optimise effective recovery from liver injury, hepatologists need to better understand how to regulate the signals that control liver repair. Growing evidence indicates that the Hedgehog (Hh) pathway is a critical regulator of adult liver repair and hence, a potential diagnostic and/or therapeutic target in cirrhosis. Although the Nobel Prize laureates Wieschaus and Nussland-Volhart described the Hh pathway in 1980, its importance in liver injury outcomes has emerged much more recently. Hh is a classic morphogen, i.e. it is secreted by ligand-producing cells, diffuses into the extracellular space and determines the fate of Hh-responsive target cells according to its concentration and the duration of exposure. Hh is crucial for embryogenesis and its name is based on evidence that genetic disruption of Hh production induces a spiculated appearance in fly larvae, causing them to resemble the homonymous mammal. The first evidence that Hh might be involved in liver disease dates from the 2001 description of Hh pathway transcripts in a liver microarray analysis of liver samples from patients with cholangiopathies. Since then, extensive evidence demonstrates that Hh pathway induction not merely associates with, but actually controls, liver disease progression, identifying this pathway as a potential therapeutic target to optimise liver repair. Herein, we summarise the preclinical and clinical data showing that Hh signalling regulates liver disease progression and we discusse potential translational applications of this new knowledge.