The liver plays vital roles in digestion, metabolism, and detoxification. Remarkably, the adult liver has a unique ability to regenerate, with a capacity to regenerate even after two-thirds of the organ is removed by partial hepatectomy. The reviews in this series explore the roles of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic stem/progenitor cells in development, repair, and pathogenesis. Improved understanding of the cellular process underlying development and regeneration may provide important insights into liver injury caused by disease and aberrant cellular replication in liver cancers. Image credit: Dr. Kenichiro Furuyama.
The liver has a unique and extraordinary capacity for regeneration, even in adult organisms. This regenerative potential has traditionally been attributed to the replicative capabilities of mature hepatocytes and cholangiocytes, though emerging evidence suggests that other resident liver cell types such as progenitors, liver sinusoidal endothelial cells, and hepatic stellate cells respond to liver injury and contribute to repair. These other cells types are also associated with liver scarring, dysfunction, and carcinogenesis, which suggests that appropriate regulation of these cells is a major determinant of response to liver injury. The Reviews in this series explore possible contributions of liver progenitor cells, liver sinusoidal endothelial cells, and hepatic stellate cells to liver homeostasis and repair and highlight how these processes can go awry in chronic liver injury, fibrosis, and liver cancer.
Anna Mae Diehl, John Chute
Liver sinusoidal endothelial cells (LSECs) have long been noted to contribute to liver regeneration after liver injury. In normal liver, the major cellular source of HGF is the hepatic stellate cell, but after liver injury, HGF expression has been thought to increase markedly in proliferating LSECs. However, emerging data suggest that even after injury, LSEC expression of HGF does not increase greatly. In contrast, bone marrow progenitor cells of LSECs (BM SPCs), which are rich in HGF, are recruited to the liver after injury. This Review examines liver regeneration from the perspective that BM SPCs that have been recruited to the liver, rather than mature LSECs, drive liver regeneration.
Laurie D. DeLeve
The liver is a complex organ that requires multiple rounds of cell fate decision for development and homeostasis throughout the lifetime. During the earliest phases of organogenesis, the liver acquires a separate lineage from the pancreas and the intestine, and subsequently, the liver bud must appropriately differentiate to form metabolic hepatocytes and cholangiocytes for proper hepatic physiology. In addition, throughout life, the liver is bombarded with chemical and pathological insults, which require the activation and correct differentiation of adult progenitor cells. This Review seeks to provide an overview of the complex signaling relationships that allow these tightly regulated processes to occur.
Luke Boulter, Wei-Yu Lu, Stuart J. Forbes
Stem cell niches are special microenvironments that maintain stem cells and control their behavior to ensure tissue homeostasis and regeneration throughout life. The liver has a high regenerative capacity that involves stem/progenitor cells when the proliferation of hepatocytes is impaired. In recent years progress has been made in the identification of potential hepatic stem cell niches. There is evidence that hepatic progenitor cells can originate from niches in the canals of Hering; in addition, the space of Disse may also serve as a stem cell niche during fetal hematopoiesis and constitute a niche for stellate cells in adults.
Claus Kordes, Dieter Häussinger
Recent advances in developmental biology have greatly expanded our understanding of progenitor cell programming and the fundamental roles that Sox9 plays in liver and pancreas organogenesis. In the last 2 years, several studies have dissected the behavior of the Sox9+ duct cells in adult organs, but conflicting results have left unanswered the long-standing question of whether physiologically functioning progenitors exist in adult liver and pancreas. On the other hand, increasing evidence suggests that duct cells function as progenitors in the tissue restoration process after injury, during which embryonic programs are sometimes reactivated. This article discusses the role of Sox9 in programming liver and pancreatic progenitors as well as controversies in the field.
Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.
Detlef Schuppan, Yong Ook Kim
Hepatic stellate cells are liver-specific mesenchymal cells that play vital roles in liver physiology and fibrogenesis. They are located in the space of Disse and maintain close interactions with sinusoidal endothelial cells and hepatic epithelial cells. It is becoming increasingly clear that hepatic stellate cells have a profound impact on the differentiation, proliferation, and morphogenesis of other hepatic cell types during liver development and regeneration. In this Review, we summarize and evaluate the recent advances in our understanding of the formation and characteristics of hepatic stellate cells, as well as their function in liver development, regeneration, and cancer. We also discuss how improved knowledge of these processes offers new perspectives for the treatment of patients with liver diseases.
Chunyue Yin, Kimberley J. Evason, Kinji Asahina, Didier Y.R. Stainier
Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.
Taro Yamashita, Xin Wei Wang