Cell Plasticity in Liver Regeneration

Abstract

The liver, whose major functional cell type is the hepatocyte, is a peculiar organ with remarkable regenerative capacity. The widely held notion that hepatic progenitor cells contribute to injury-induced liver regeneration has long been debated. However, multiple lines of evidence suggest that the plasticity of differentiated cells is a major mechanism for the cell source in injury-induced liver regeneration. Investigating cell plasticity could potentially expand our understanding of liver physiology and facilitate the development of new therapies for liver diseases. In this review, we summarize the cell sources for hepatocyte regeneration and the clinical relevance of cell plasticity for human liver diseases. We focus on mechanistic insights on the injury-induced cell plasticity of hepatocytes and biliary epithelial cells and discuss future directions for investigation. Specifically, we propose the notion of 'reprogramming competence' to explain the plasticity of differentiated hepatocytes. Liver Regeneration and Cell PlasticityThe liver harbors remarkable regenerative capacity and performs multiple physiological functions [1,2]. However, as this organ is central for metabolism and detoxification, it often suffers extraneous injury and gradually loses its regenerative ability [1,2]. Understanding the mechanisms of liver regeneration is a fundamental topic in liver biology. Since hepatocytes are the primary effector cells for liver physiological functions, the cell source for new hepatocytes after injury has been a main focus in liver regeneration research. It has long been debated whether stem cells contribute to injury-induced liver regeneration. However, recent studies have shown that cell sources other than stem cells also contribute to injury-induced liver regeneration [3]. Cell reprogrammingthat is, the plasticity of hepatocytes and biliary epithelial cellshas been identified as a major pathway to generate new hepatocytes in response to liver injury. Therefore, a better understanding of the underlying mechanisms of injury-induced cell plasticity in vivo may facilitate the development of cell-plasticitybased therapies. In this review, we summarize the latest findings on cell sources with mechanistic regulation in liver regeneration and discuss their clinical relevance to human liver diseases. Liver Homeostasis under Physiological ConditionsIt has long been proposed that the liver harbors liver progenitor cells (LPCs) in the canal of Hering, a structure that connects bile canaliculi with bile ducts in periportal areas, to fulfil liver regeneration requirements under normal physiological conditions [2]. LPCs are characterized based on the following properties: (i) clonogenic ability with high proliferation potential; (ii) the ability to differentiate into both hepatocytes and cholangiocytes under culture conditions; and (iii) liver repopulation ability after transplantation [2]. The 'streaming liver' model was proposed decades ago to describe the contribution of LPCs to in vivo liver homeostasis. This model de...

Robust expansion and functional maturation of human hepatoblasts by chemical strategy

“…HBs proliferate vigorously and remain bipotent at the liver bud stage during embryogenesis, which is influenced by signals from the surrounding mesenchyme. Similarly, expansion and maintenance of HBs identity in vitro are highly dependent on precise regulation by extrinsic and intrinsic signals [21]. Previous studies have demonstrated that stimulation of Wnt and inhibition of TGF-β were both important for hepatic proliferation [7,14,22].…”

Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling

“…Cell plasticity is also implicated in non-nutritional physiological responses. During chronic periportal liver injury, hepatocytes de-differentiate into liver progenitor-like cells simultaneously expressing markers for hepatocytes and biliary epithelial cells and regenerate hepatocytes and duct-like cells [ 78 ]. These examples suggest that alterations in cellular identity may play an important role in physiological and pathological responses implicated in a broad range of human diseases.…”

Cholangiogenic potential of human deciduous pulp stem cell-converted hepatocyte-like cells

“…HPCs are responsible for developing CPCs and cholangiocytes [26]. Hepatocytes exhibit plasticity to recruit bile ductular cells under liver physiological and pathological conditions [34]. Transplanted hepatocytes can differentiate into bile ductular cells in bile duct ligation model animals [35].…”