β cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo

Abstract

Inflammatory injury to the pancreas results in regeneration of normal tissue and formation of metaplastic lesions of a ductal phenotype. These metaplastic ductal lesions (MDL) are called tubular complexes (TC), mucinous metaplasia, or pancreatic intraepithelial neoplasia. Because they are regularly found in chronic pancreatitis and pancreatic cancer, their formation is thought to represent a step in inflammation-mediated carcinogenesis. Despite these lesions' ductal character, their origin is controversial. All known pancreatic cell lineages have been suggested as the origin. In vitro studies suggest that differentiated cells in the pancreas remain highly plastic and can transdifferentiate as a mechanism of regeneration and metaplasia. In vivo studies suggest that islets, specifically ␤ cells, may be the cell of origin. However, in vitro studies are subject to ductal cell contamination, and previous in vivo studies interpret static data rather than direct evidence. Using genetic lineage tracing in vivo, we investigate whether transdifferentiation of ␤ cells contributes to regeneration or metaplasia in pancreatitis. RIP-CreER;Z/AP mice were used to heritably tag ␤ cells in the adult pancreas. Injury by cerulein pancreatitis resulted in regeneration of normal tissue and metaplasia with formation of two distinct types of TC and mucinous lesions. Lineage tracing revealed that none of these MDL are of ␤ cell origin; nor do ␤ cells contribute to regeneration of normal acinar and ductal tissue, which indicates that the plasticity of differentiated pancreatic islet cells, suggested by earlier static and in vitro studies, plays no role in regeneration, metaplasia, and carcinogenesis in vivo.metaplasia ͉ pancreatitis ͉ pancreatic intraepithelial neoplasia T issue injury can result in regeneration of normal tissue and in metaplasia. Metaplasia is often seen in response to chronic injury and can occur by selective cellular proliferation or death or by transdifferentiation. Cell lineages in the pancreas include exocrine (acinar and ductal) and endocrine cells. Inflammation of the pancreas results in the formation of metaplastic lesions of a ductal phenotype (MDL) that are consistently found in chronic pancreatitis (CP) and specimens of pancreatic cancer. Therefore, this ''ductal'' metaplasia is thought to represent a condition with increased risk of neoplasia. In the literature, two definitions have been used to describe MDL in the pancreas: tubular complexes (TC) and mucinous metaplasia or pancreatic intraepithelial neoplasia (PanIN) (1, 2). TC, defined as cylindrical tubes with a wide lumen lined by a monolayer of flat duct-like cells (3-5), are found in pancreatic development, regeneration, in CP, and in cancer (5-8). In some studies, TC exhibited a high cell turnover and were thought to have regenerative potential, including islet regeneration (5, 9). A progression of TC to neoplasia has been suggested in rodent models of chemical carcinogenesis (1, 10, 11) and transgenic mouse models (12). Misexpression of mucins in pan...

Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice

“…In contrast, rigorous in vivo lineage tracing studies have established that transdifferentiation of acinar cells into nouveau ␤-cells or ductal epithelium is, for the most part, absent (26,27). This mirrors the inability of regenerating ␤-cells to undergo transdifferentiation into exocrine tissues (28,29), reinforcing the existence of a ''like begets like'' plasticity in the adult pancreas. One notable exception to these observations occurs in the setting of chronic cerulein-mediated injury, wherein a minor subpopulation of metaplastic ductal epithelium is, in fact, derived via transdifferentiation of acinar cells (27).…”

Role of Cadherin-mediated Cell-Cell Adhesion in Pancreatic Exocrine-to-Endocrine Transdifferentiation

“…However, direct evidence in vivo has been provided only for acinar-to-ductal transdifferentiation in transgenic mice having persistent expression of Pdx1 in the pancreatic acinar cells (15). In addition, recent studies have failed to detect any transdifferentiation events of pancreatic acinar cells either in normal or in pathological conditions (29,30). Indeed, pancreatic ␤-cells are reported to be maintained predominantly by self-replication in adult mice (31)(32)(33).…”

Non-β-cell progenitors of β-cells in pregnant mice

“…This is similar to conclusions reached after induction of acute pancreatitis. 35 However, we cannot exclude that transdifferentiation could take place during a much longer period following the tamoxifen pulse, or under different conditions, for example following pancreatic injury and regeneration. The hpAp labelling index in non-pregnant control and pregnant female animal pancreata was calculated by forming the ratio of total number of pixels of cross-sectional area immunostained for hpAp to total number of pixels cross-sectional area immunostained for insulin, using Image J.…”