Liver stem cells: the fall and rise of tissue biology.

The first reports of marrow-derived hepatocytes are only a few years old,1-4 and both information and controversy have since proliferated. Considerable experimental literature has been published (reviewed in Alison et al.5) as have a few human, largely confirmatory studies,6-8 the newest of which, by Ng et al., appears in this issue of HEPATOLOGY.9 The first studies focused on the most dramatic, dogma-bursting findings: marrow-derived hepatocytes and cholangiocytes. This recent study hints at broader developments, the focus not on marrowderived hepatobiliary cells alone, but also on other cell compartments, in particular, monocytes and endothelium. In part, the importance of a broader inquiry is an understanding that movement of cells from one organ to another is part of complex, orchestrated processes at a tissue level, rather than relying solely on cellular or molecular mechanisms. This is a reversal of a trend spanning centuries, now starting to show its age, of progressive, analytical dissection of organisms into smaller and smaller components. Surface observation of the body gave way to examination of the interior, then gross anatomy yielded to microanatomy and histology, then to cellular and, eventually, triumphantly, to molecular biology. With the mapping of the human genome, the successes of ever-finer dissection are clear. However, a bias has risen where scientific data is best expressed as products of molecular analysis. A seldom discussed aspect of reports of in vivo cell plasticity is the reliance on photomicrographs as essential data. These images were not merely supporting players or attempts to secure a spot on the journal’s cover (though I’ll be the first to admit of the latter’s success), they were the whole point. They showed transplanted, “transdifferentiated” cells engrafted structurally and functionally into tissue, pointing to a renewed focus on tissue biology, for which cellular and molecular biology would now be the supporting players. Early criticisms of plasticity research were raised by cell and molecular biologists insisting on “proof” that pertained more to their own fields, not to phenomena at a tissue level. For example, early calls for demonstration of clonality, robustness, and functionality to prove in vivo plasticity10,11 were applications of criteria important for examining cells in culture, but with less relevance to tissue biological processes. Ex vivo demonstration of plasticity required clonality and robustness of effects to rule out phenomena arising from low-level contaminant cell populations. Function is most important for ex vivo cell typing, because without tissue integration, markers alone are unreliable. But in vivo, at a tissular level, small numbers of cells may play roles that are important far beyond their number; functional and structural organization counts as much as quantity (if not more so); and integration into and maintenance of tissue structure is, in fact, a demonstration of function. What is meant by “tissue biology?” Biological investigation of the interactions of diverse cellular compartments, arrayed in normal or pathologically altered, microanatomic juxtapositions, in 3 spatial dimensions and over time. As complicated as this sounds, it is not more than burgeoning studies in proteomics, for example. Indeed, the last few months have seen many exciting studies from investigators taking such a tissue-level approach. For example, stromal derived factor 1 (SDF-1), once thought to be produced only by marrow stromal cells as a homing mechanism for CXCR4 , marrow-directed hematopoietic stem cells, was shown by Hatch et al. to be also produced by hepatobiliary cells in severely injured liver, perhaps as an attractant for circulating hepatic progenitors.12 Kollet et al., in an extraordinarily broad, yet finely detailed study, have recently shown that interplay of SDF-1, matrix metalloproteinase 2 (MMP-2), MMP-9, and hepatocyte growth factor are responsible for recruiting CD34 circulating cells to the liver in response to injury.13 Whereas SDF-1 is produced by the injured or regenerating hepatic epithelia, the other factors are produced by stellate cells. Prior studies also showed that biliary cells in normal as well as reactive tissue are c-kit 14,15 and that stem cell factor (SCF), the ligand for c-kit, is produced by stellate cells.16 Now, Simpson et al. have shown that SCF production rises after acute acetaminophen injury, where blocking with anti-SCF antibodies can lead to increased lethality.17 Administration of SCF will not only rescue the Abbreviations: SDF, stromal derived factor; MMP, matrix metalloproteinase; SCF, stem cell factor; FAH, fumarylacetoacetate. From the Division of Digestive Diseases, Department of Medicine, Department of Pathology, Beth Israel Medical Center, New York, NY. Address reprint requests to: Neil D. Theise, M.D., Division of Digestive Diseases, Department of Medicine, Department of Pathology, Beth Israel Medical Center, First Ave. at 16th St., New York, NY 10003. E-mail: [email protected]; fax: 212-420-4373. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3804-0004$30.00/0 doi:10.1053/jhep.2003.50465