Hepatic Stem Cells

The overall goal of this issue of Seminars in Liver Diseases is to provide the reader with insight into the experimental evidence for liver stem cells, some of their major features, and their capacity to repopulate the liver depleted of parenchymal cells, as well as some of the major controversies about their origin and mechanism of forming liver parenchymal cells. The articles were selected to provide hepatologists with a sampling of current opinions about liver stem cells. Liver was one of the first tissues composed of normally long-lived parenchymal cells in which stem cells were identified in adult animals, but there was almost universal skepticism regarding the role of liver stem cells in the physiopathology of the liver and many even doubted their existence. The liver simply did not seem to need stem cells because even extensive tissue loss was readily repaired by the rapid proliferation of both hepatocytes and cholangiocytes, coupled with the coordinated repair of vessels and tissue matrix. A cascade of recent studies has almost erased the skepticism about the existence of liver stem cells in adult animals, but insight into the nature and location of the stem cells is incomplete and knowledge of the molecular mechanisms that regulate their activation, differentiation, and proliferation is lacking almost entirely. As a consequence, the latter topics retain considerable controversy.

This situation explains why the articles highlighted in this issue of Seminars focus on experimental studies, and why most of them discuss experiments performed in animals or in ex vivo cell cultures. Laboratory studies form the basis of our current understanding of the possible nature(s) of liver stem cells, and they provide an early glimpse of possible molecular mechanisms that are involved in the generation of new lineages of hepatocytes and cholangiocytes from stem cells. Thorgeirsson and Grisham provide a brief overview of the literature on studies employing laboratory animals that updates their previous review of liver stem cells. Weiss and Strick-Marchand consider some of the advantages of ex vivo studies using cell culture. Alison discusses the differentiation capacities of liver stem cells and molecular regulatory molecules that are likely to be involved. Zheng et al highlight their studies on the selective isolation of cells from livers of fetal mice, based on expression of surface antigens, and demonstrate the capability of these cells to generate hepatocytes and other epithelial lineages after transplantation in vivo. Dabeva and Shafritz discuss studies on the capability of different types of liver-derived cells to repopulate the liver when transplanted. Grompe reviews the experimental evidence that hematopoietic stem cells are the true stem cells for epithelial lineages in the liver.

Examination of human tissues suggests that the properties of liver stem cells of laboratory animals and humans are generally similar. Putative liver stem cells appear to be involved in the repair of the human liver affected by several types of chronic damage and in the pathogenesis of hepatocellular neoplasms as well. Progress in isolating putative human liver stem cells is being made, in analogy to stem sells of laboratory animals. Strain et al and Roskams present studies on the identification of cells in diseased human livers that express properties of liver stem cells. Strain et al evaluate some of the phenotypic properties of these types of cells when isolated and examined ex vivo, and Roskams provides evidence associating such cells with a variety of reparative and neoplastic processes in human liver.

Laboratory studies suggest the possibility that liver stem cells may ultimately have therapeutic use in the treatment of some hepatic functional deficiencies in humans, but this event is a long way off. It is sobering to recall the lag between demonstrating the rescue of lethally irradiated mice with bone marrow transplants and the widespread use of bone marrow stem cell transplants in humans. Nevertheless, we believe that the reader will perceive that significant progress toward the achievement of this goal- the use of liver stem cells to correct hepatic cellular and metabolic deficiencies-has been made. After perusing this issue, the reader should perceive the fundamental similarities of putative liver stem cells in humans and experimental animals. Liver stem cells are likely to play important roles in the pathogenesis of various human liver diseases and, ultimately, in the therapy of some of them.