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New kids on the block: pancreatic stellate cells enter the fibrogenesis world
  1. M PINZANI
  1. Dipartimento di Medicina Interna,
  2. Universita degli Studi di Firenze,
  3. Viale G.B. Morgagni, 85,
  4. I-50134 Firenze, Italy
  5. Email: m.pinzani{at}dfc.unifi.it

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See article on page 534

Two recently published papers have shown that a cell type with morphological features of “vitamin A storing” stellate cells is present in rat and human pancreatic tissue.1 2 These observations add to previous reports addressing the same issue in several other extrahepatic organs, including the lung, the intestine, and the kidney.3 4

Over the past 10 years, a great deal of scientific information has followed the identification of stellate cells as the main cell type involved in the progression of liver fibrosis following chronic tissue damage.5 Several roles for this cell type in normal and diseased liver have been highlighted. In addition to storage of vitamin A, these include: (1) excessive deposition of extracellular matrix on activation; (2) modulation of sinusoidal tone in normal liver as a result of their contractile features and possible involvement in the progression of portal hypertension; (3) synthesis of soluble factors affecting liver regeneration (hepatocyte growth factor) or recruitment and differentiation of inflammatory cells; and (4) a possible role in the development of primary and metastatic liver cancer stroma. Most experimental evidence, originally produced in vitro, has subsequently been corroborated by extensive studies in animal models and in tissue sections obtained from patients with different degrees of necroinflammatory and fibrogenic activity. More recently, a consistent number of studies have focused on the intracellular signalling events related to hepatic stellate cell activation, proliferation, migration, synthesis of the extracellular matrix (ECM), and adhesion. The results of these studies have opened new perspectives in the development of pharmacological strategies aimed at modulating the fibrogenic process within the liver. Along these lines, after the initial identification and characterisation of pancreatic stellate cells, the work by Apte and coworkers (see page 534) has been directed at verifying whether these cells, maintained in culture, produce collagen and other ECM components and respond to profibrogenic growth factors such as platelet derived growth factor (PDGF) and transforming growth factor (TGF) β1, similarly to their hepatic counterparts.6 The results of the study support the concept that pancreatic stellate cells may play a key role in the development of pancreatic fibrosis and open new perspectives in this specific area of research. Recent preliminary data indicate that increased formation of lipid peroxidation products, particularly reactive aldehydes, able to form adducts with acinar cell proteins occurs in one of the most common clinical conditions associated with pancreatic fibrosis, namely chronic alcoholic pancreatitis.7 Studies performed in human hepatic stellate cells have shown that reactive aldehydes such as 4-hydroxy-2, 3-nonenal and other 4-hydroxy-2, 3-alkenals of different chain lengths are able to stimulate procollagen type I synthesis and secretion at concentrations which are compatible with a mild to moderate oxidative stress (i.e. lipid peroxidation) occurring in vivo.8 It must be stressed that the profibrogenic effects of these products, derived from the lipoperoxidative damage of membrane phospholipids, are independent of the more articulated mechanisms involved in chronic tissue repair (tissue damage > inflammatory infiltration > release of profibrogenic growth factors). Along these lines, it would be important to evaluate the role of these compounds in periacinar stellate cell activation and ECM synthesis in future studies. Beyond this important advancement there are other relevant considerations. As already proposed, the presence of stellate cells in several organs and tissues raises the possibility of a “vitamin A storing system”.9 In addition, similarly to hepatic stellate cells, stellate cells in extrahepatic tissues are distributed with specific interstitial features, namely their cytoplasmic projections encircle sinusoidal-like vascular structures. It is therefore possible that stellate cells constitute a class of organ specific pericytes with similar physiological and pathophysiological implications. In this context, a key current issue concerns the origin of this cell type. Because these cells express desmin and smooth muscle α-actin, they were assumed to be of myogenic origin. This hypothesis became doubtful when it was reported that stellate cells also express glial fibrillary acidic protein (GFAP) and neural cell adhesion molecule (NCAM). Moreover, recent work by Niki and coworkers has demonstrated that activated hepatic stellate cells express nestin, a class VI intermediate filament protein originally identified as a marker for neural stem cells.10 It is generally accepted that cephalic neural crest cells give rise to a variety of cell types, including neurones, glial cells, cartilage, bone, and smooth muscle cells. Consequently, the key question is whether there a common precursor cell somewhere in the neural crest that gives rise to all “stellate cells”. It is obvious that further studies on the embryonic origin of these cells are required.

Researchers in the field of hepatic stellate cells are not alone anymore. There are new kids on the block. Good luck!

See article on page 534

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