Faculty Bibliography

This issue of Pediatric Diabetes contains articles with scientific data, their interpretation, and a discussion of the respective field of stem cells and diabetes - its achievements and controversies. Through our daily laboratory activities, we employ a reductionist approach and often a deterministic interpretation of data. We would like to make this contribution a means of adding a somewhat different perspective to this collection of essays. This conceptual piece is merely intended to be an invitation to further thoughts and discussions.

Hepatic oval stem cells have been identified under physiological and more often after severe liver injury when the proliferation of existing hepatocytes has been inhibited. Oval cells are bipotential progenitors of the two major epithelial cell types in the liver: hepatocytes and cholangiocytes (i.e., bile duct lining cells). The origins of oval cells have been much debated. They have been proposed to be the result of hepatocyte dedifferentiation or of small, resident cholangiocytes or periductal cells, or to be derived, from hematopoietic stem cells. Hepatic oval cells have the ability to repair damaged liver on a par with native hepatocytes. As such, oval cells would present a means of cellular therapy in liver injury. Intriguingly, hematopoietic stem cells from bone marrow and cord blood have recently been shown to be a source of both hepatic oval cells and hepatocytes, with the ability to reconstitute injured liver. These findings have, however, been the subject of extensive controversy, with confounding studies and hypotheses abounding in the literature. This article reviews the data regarding the location, characterization, and function of hepatic oval cells, and also discusses the controversies surrounding transdifferentiation and fusion of hematopoietic stem cells during their contribution to hepatocytes

CONTEXT: Curative therapy for diabetes mellitus mainly implies replacement of functional insulin-producing pancreatic beta cells, with pancreas or islet-cell transplants. However, shortage of donor organs spurs research into alternative means of generating beta cells from islet expansion, encapsulated islet xenografts, human islet cell-lines, and stem cells. Stem-cell therapy here implies the replacement of diseased or lost cells from progeny of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell mass of a blastocyst) and adult stem cells (found in the postnatal organism) have been used to generate surrogate beta cells or otherwise restore beta-cell functioning. STARTING POINT: Recently, Andreas Lechner and colleagues failed to see transdifferentiation into pancreatic beta cells after transplantation of bone-marrow cells into mice (Diabetes 2004; 53: 616-23). Last year, Jayaraj Rajagopal and colleagues failed to derive beta cells from embryonic stem cells (Science 2003; 299: 363). However, others have seen such effects. WHERE NEXT? As in every emerging field in biology, early reports seem confusing and conflicting. Embryonic and adult stem cells are potential sources for beta-cell replacement and merit further scientific investigation. Discrepancies between different results need to be reconciled. Fundamental processes in determining the differentiation pathways of stem cells remain to be elucidated, so that rigorous and reliable differentiation protocols can be established. Encouraging studies in rodent models may ultimately set the stage for large-animal studies and translational investigation

Liver parenchymal maintenance and regeneration after injury are physiologically supported by 3 cell compartments: mature liver cells, intra-organ stem cells such as cells of the proximal biliary tree and periductal cells, and extra-organ stem cells from the circulation and the bone marrow. In the latter case, hepatocyte derivation from circulating cells (plasticity) can arise via direct transdifferentiation (site specific, receptor/ligand dependent) or by fusion of circulating cells with pre-existing hepatocytes. Other non-physiologic stem cells, such as mesenchymal stem cells from the bone marrow and embryonic stem cells, may be potentially used in treatment of inherited and acquired liver diseases. This review updates our current understanding of these various cell populations and of possible approaches to their future therapeutic uses in cell transplantation, bioartificial liver devices, cytokine/chemokines manipulation of physiological repair pathways, and gene therapy

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field

Methotrexate treatment for psoriasis is known to cause hepatic fibrosis in some patients, which might progress to cirrhosis. The fine, radiating, fibrous septa developing in this setting have a distribution that is reminiscent of the location of the canals of Hering (coH). To assess the possibility of fibrous obliteration of the coH in patients receiving methotrexate, we developed a staining technique by combining an immunohistochemical stain for cytokeratin 7 with a modified Masson trichrome. Sixteen biopsy specimens from 7 patients were evaluated. The biopsies had a variety of histologic changes, including steatosis, anisonucleosis, multinucleation, chronic inflammation, bile duct damage, and ductular reaction. Fibrosis was present in 13 biopsy specimens (81%) and was mild in 7, moderate in 3, and severe in 3 specimens. Compared with normal (control) liver specimens, biopsy specimensfrom patients receiving methotrexate had decreased numbers of coH (1.9 +/- 0.8 vs 5.2 +/- 1.7; P < .025). In specimens with moderate or severe fibrosis, fibrous septa sometimes extended along the coH. These findings suggest that scarring of the coH might be a consequence of the toxic effects of methotrexate

Stem cells may be considered complex reactive systems because of their vast number in a living system, their reactive nature, and the influence of local environmental factors (such as the state of neighboring cells, tissue matrix, stem cell physiological processes) on their behavior. In such systems, emergent global behavior arises through the multitude of local interactions among the cell agents. Approaching hematopoietic and other stem cell lineages from this perspective have critical ramifications on current thinking relating to the plasticity of these lineage systems, the modeling of stem cell systems, and the interpretation of clinical data regarding many diseases within such models

It may be argued that adult stem cell processes or, more precisely, the cell lineages that arise from them, represent complex reactive or adaptive systems. Approaching hematopoietic and other stem cell lineages from this perspective has direct bearing on current debates regarding the plasticity of these lineage systems as well as on interpretation and modeling of clinical data regarding many diseases