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Current Consensus and Discussion on Pancreatic Stellate Cell Research

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Gut Online First, published on November 24, 2011 as 10.1136/gutjnl-2011-301220 Leading article Gut: first published as 10.1136/gutjnl-2011-301220 on 24 November 2011. Downloaded from extending along the base of adjacent StellaTUM: current consensus acinar cells similar to that of pericytes in the mammary gland. In health, PSC exist in their quiescent phenotype and exhibit and discussion on pancreatic the presence of abundant vitamin A-containing lipid droplets in their cyto- stellate cell research plasm. It is estimated that quiescent PSC form 4e7% of all parenchymal cells in the 1 2 3 normal pancreas.45During pancreatic Mert Erkan, Guido Adler, Minoti V Apte, injury, resident PSC transform into an Max G Bachem,4 Malte Buchholz,5 So¨nke Detlefsen,6 activated phenotype that secretes exces- 7 1 5 sive amounts of the extracellular matrix Irene Esposito, Helmut Friess, Thomas M Gress, (ECM) proteins that comprise fibrous 4 8 9 tissue. Recent evidence suggests that Hans-Joerg Habisch, Rosa F Hwang, Robert Jaster, a small proportion of activated PSC may 1 7 10 also be derived from circulating bone Jo¨rg Kleeff, Gu¨nter Klo¨ppel, Claus Kordes, marrow (BM)-derived cells that home to 8 11 Craig D Logsdon, Atsushi Masamune, the pancreas during pancreatic injury. 1 12 Christoph W Michalski, Junseo Oh, STELLATE CELL SYSTEM AND THE ORIGIN 3 13 OF PSC AND HSC Phoebe A Phillips, Massimo Pinzani, In the human body, the stellate cell system Carolin Reiser-Erkan,1 Hidekazu Tsukamoto,14 consists of retinoid-storing cells in various 3 organs, including the liver, pancreas, lung, Jeremy Wilson kidney, intestine, spleen, adrenal gland, ductus deferens and vocal cords showing a perivascular location with a distribution 67 The field of pancreatic stellate cell (PSC) into elucidating the biology and function of typical of a pericyte. However, the origin biology is very young, as the essential in- these cells. It is now well established that of stellate cells is still being debated. 8e10 11 12 vitro tools to study these cells (ie, methods PSC are responsible for producing the Mesenchymal, endodermal as well 13e15 to isolate and culture PSC) were only stromal reaction (fibrosis) of two major as neuroectodermal origins are developed as recently as in 1998. Nonethe- diseases of the pancreasdchronic pancrea- suggested. Neuroectoderm and mesoderm less, there has been an exponential increase titis and pancreatic cancer. Despite expo- were considered as two potential origins of d http://gut.bmj.com/ in research output in this field over the past nentially increasing data, the methods for HSC these cells and PSC share numerous decade, with numerous research groups studying PSC remain variable. Although characteristics as indicated by morpholog- around the world focusing their energies within individual laboratories methods are ical, functional and gene expression fi consistent, different methodologies used by studies. Expression pro ling of PSC, HSC fi various research groups make it difficult to and broblasts has demonstrated that PSC 1Department of Surgery, Klinikum rechts der Isar, TU and HSC are distinctly different from 2 compare results and conclusions. This Mu¨nchen, Munich, Germany; Department of Internal fibroblasts, but share many homologies article is not a review article on the func- on September 27, 2021 by guest. Protected copyright. Medicine, Johannes Gutenberg-Universita¨t Mainz, including the expression of genes related to Mainz, Germany; 3Faculty of Medicine, The University of tions of PSC. Instead, members of the New South Wales, Sydney, New South Wales, Pancreatic Star Alliance (http://www. ECM proteins, contractility, retinoid Australia; 4Department of Clinical Chemistry, pancreaticstaralliance.com) discuss here metabolism (although lower retinoid 5 Universita¨tsklinikum Ulm, Ulm, Germany; Department of and consolidate current knowledge, to content in PSC compared with HSC) and Internal Meidicine, Universita¨tsklinikum Marburg, 16 6 outline and delineate areas of consensus or growth factors. In fact, both cells (in Marburg, Germany; Department of Pathology, Odense fi University Hospital, Odense, Denmark; 7Institute of otherwise (eg, with regard to methodolog- comparison with broblasts) have more 17 Pathology, Klinikum rechts der Isar, TU Mu¨nchen, ical approaches) and, more importantly, to similarities than differences. It is there- 8 Munich, Germany; Department of Surgical Oncology, identify essential directions for future fore possible that HSC and PSC share University of Texas MD Anderson Cancer Center, 9 research. a common origin. Houston, Texas, USA; Department of Internal Medicine, The neuroectoderm proposal for the University of Rostock, Rostock, Germany; 10Department of Gastroenterology, Hepatology and Infectious PANCREATIC STELLATE CELLS origins of HSC was refuted by a study by 10 Diseases, Universita¨tsklinikum Du¨sseldorf, Du¨sseldorf, Hepatic stellate cells (HSC) were first Cassiman et al, who used a genetic cell Germany; 11Division of Gastroenterology, Tohoku described by Karl von Kupffer in 1876; lineage mapping technique with University Graduate School of Medicine, Sendai, Miyagi, flox 12 however, similar cells in the pancreas were Rosa26YFP mice crossed with mice Tohoku, Japan; Laboratory of Cellular Oncology, Korea fi 1e3 University Graduate School of Medicine, Seoul, South rst observed in the 1980s. In 1998, expressing Cre under the control of 4 5 Korea; 13Department of Internal Medicine, University of Apte et al and Bachem et al isolated and the neural crest-specific Wnt1 promoter/ Florence, Florence, Italy; 14Southern California Research cultured PSC.45In the normal pancreas, enhancer. Definitive novel evidence for Center for ALPD and Cirrhosis, Keck School of Medicine PSC are located in close proximity to the the mesodermal origin of HSC has of the University of Southern California, Los Angeles, basal aspect of pancreatic acinar cells. In recently been presented by Asahina and California, USA sections immunostained for the marker colleagues818with the use of the meso- Correspondence to Dr Mert Erkan, Department of fi General Surgery, Technische Universita¨tMunchen, desmin (a cytoskeletal protein), quiescent derm-speci c MesP1Cre. A conditional ¨ CreERT Klinikum rechts der Isar, 81675 Munich, Germany; PSC can be seen as cells with a central cell cell lineage analysis using Wt1 / fl fl [email protected] body and long cytoplasmic projections Rosa26LacZ ox or ROSA26mTmG ox mice, CopyrightErkan M, Adler Article G, Apte author MV, et al. Gut(or(2011). their doi:10.1136/gutjnl-2011-301220 employer) 2011. Produced by BMJ Publishing Group Ltd (& BSG) under licence.1of7 Leading article Gut: first published as 10.1136/gutjnl-2011-301220 on 24 November 2011. Downloaded from revealed Wt1-positive septum transversum as nestin and CD133, which are known to colleagues4 from Professor Wilson’s labo- giving rise to mesothelial cells, submeso- be expressed on somatic stem cells.24 ratory in 1998. This method took advan- thelial cells, HSC and perivascular mesen- However, before HSC can be classified as tage of the known vitamin A content chymal cells during liver development.8 stem cells, essential characteristics of stem (stored in cytoplasmic lipid droplets) of That study also demonstrated Wt1-posi- cells should be defined and verified in stel- PSC, which allowed the cells to be sepa- tive mesothelial/submesothelial cells late cells. Briefly, stem cells are undifferen- rated by a single density gradient method migrating inward from the liver surface to tiated cells with the potential to proliferate using nycodenz. More recently, a similar generate liver mesenchymal cells including and to undergo developmental processes. method (albeit with some modifications) HSC. Similar lineage tracing techniques More specifically, stem cells: (1) express was used to isolate quiescent PSC from need to be used to determine the exact genes required for the inhibition or induc- normal human pancreas.28 The gradients origin of PSC. tion of cell development; (2) maintain their can be developed not only with nycodenz characteristics in a special microenviron- but also with other colloids such as ROLE OF PSC IN FIBROSIS AND ment (stem cell niche); (3) are normally percoll, iohexol, iodixanol, optiprep. The REGENERATION quiescent, but can be activated on demand; average yield of cells from a rat pancreas is The origin and fate of stellate cells in the (4) proliferate/migrate when activated; and approximately 3 million cells per gram of context of injury and regeneration are also (5) can differentiate into effector cells pancreas. The yield of PSC is much lower a matter of ongoing debate. Regarding (plasticity) or influence the developmental from human pancreas due to limited the contribution of BM and epithelial fate of other cells. Through these mecha- tissue availability and due to the higher mesenchymal transition (EMT) of acinar nisms stem cells participate in ontogenesis, amount of fatty tissue surrounding the cells to the PSC population, the data are regeneration or reproduction of organisms. resected pancreas (compared with rat limited and restricted to studies in mice. In Furthermore, stem cells are transplantable pancreas), which can impede tissue diges- 2006, it was reported that BM is a source and can survive for a long time within host tion. PSC can also be isolated from of myofibroblast-like cells in fibrotic tissues. First steps were made to unravel cancerous or fibrotic human pancreas, as liver tissue, but the involvement of these these characteristics
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