Special articleStrategies for liver support: from stem cells to xenotransplantation
Introduction
The continuing shortage of donor organs has been a major roadblock in orthotopic liver transplantation (OLT). This has led to the consideration of several potentially viable alternatives, including bioartificial and nonbiological liver assist devices, transplantation of mature hepatocytes or of stem/progenitor cells, and potential of transplanting xenogeneic organs and cells. Numerous investigators throughout the world are engaged in these investigations and the pace of discovery has begun to accelerate in recent years. To obtain an overview of progress in these areas, EASL sponsored a Monothematic Conference, which was held in Venice on 25th-26th September 2003.
This conference was characterized by the enthusiastic participation of many leading investigators from various parts of the world. The present paper is a summary of the Monothematic Conference, including the related discussion and highlights some of the controversies in the areas of stem cells and transplantation. Since any such summary obviously cannot do full justice to the presentations and discussions at the conference, we apologize in advance for inadvertent omissions or lack of suitable emphasis on specific points.
The conference was divided into several major sessions dealing with the biology of stem cells and nonparenchymal liver cells; basic aspects of hepatocyte transplantation; genetic and other manipulations of cells from the perspective of clinical applications; hepatocyte transplantation in people; and strategies for engineering bioartificial liver and nonbiological liver support devices. Moreover, several investigators presented ongoing research in relevant areas of stem cell biology.
Section snippets
General principles concerning modification of cells
Insights into mechanisms of cell engraftment and proliferation are critical for cell therapy. In animals, transplanted cells can repopulate the liver following injury or inhibition of proliferation in native cells with various manipulations [1], [2], [3], [4], [5], [6]. Dr. S. Gupta provided an overview of mechanisms concerning transplanted cell engraftment and proliferation. Also, he reviewed suitable targets for liver cell therapy, which extend from metabolic disorders, e.g. Crigler-Najjar
Potential of stem cells and mechanisms in liver regeneration
Identification of suitable additional sources of cells that could be transplanted in lieu of hepatocytes should be effective for cell therapy applications. In this pursuit, attention has been focused on embryonic stem (ES) cells and nonhepatic stem cells.
Immunological mechanisms involving hepatic dendritic and endothelial cells
The liver is an immunologically active organ and Dr. D. Adams reviewed this area. The liver is constantly exposed to gut antigens via the portal vein, to local pathogens via the biliary tree, and to systemic pathogens via the hepatic artery. Analysis of T cells in the liver following exposure to cytomegalovirus identified presence of specific CD8+T cell fractions, including long-lived viral memory cells that are sequestered in the liver [43], [44]. The nature of the cytokine and costimulatory
Role of hepatic stellate cells in tissue remodeling
Insights into the regulation of stromal development and maintenance will facilitate tissue engineering. Also, interactions among parenchymal cells and other cells are often modulated by stromal elements. Dr. M. Pinzani reviewed the biology of the hepatic stroma and the role of hepatic stellate cells in this process. Inflammatory, infectious and other processes can all damage the stroma and in response to these processes, cells capable of producing extracellular matrix components (ECM) are often
Challenges in transplanting cells in patients, liver support systems and xenografts
The ability to cryopreserve cells is critical for clinical programs so that cell preparations can be characterized beforehand and cells can be transplanted under better controlled settings. Transplantation of freshly isolated cells is beset with difficulties concerning the unpredictability of donor organ availability and eventual viability of cells. The general goal of cell cryopreservation is to obtain the highest viability of cells after thawing. In practice, the viability of cryopreserved
Conclusions
This EASL Monothematic Conference helped to focus attention on recent progress in mechanisms regulating liver regeneration, the role of hepatic stem cells in liver regeneration, and the potential various types of extrahepatic stem cells in liver regeneration. The impact of cell transplantation and xenotransplantation in human disease was reviewed. Finally, progress in the areas of liver bioassist devices and other devices was discussed. The general agreement was that further work is needed to
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