Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice

Abstract

In multiple systems, impaired proteolysis associated with the loss of the hemostatic factor plasminogen (Plg) results in fibrin-dependent defects in tissue repair. However, repair within the liver is known to be defective in Plg-deficient (Plg o ) mice independent of fibrin clearance and appears to be compromised in part by the poor clearance of necrotic cells. Based on these findings, we examined the hepatic transcriptome after injury in search of transcriptional programs that are sensitive to the Plg͞fibrinogen system. To this end, we generated biotinylated cRNA pools from livers of Plg o mice and controls before and after a single dose of the hepatotoxin carbon tetrachloride and hybridized them against high-density oligonucleotide arrays. Analysis of the gene expression platform identified an unexpected transcriptional signature within challenged livers of Plg o mice for pancreatic gene products, including trypsinogen-2, amylase-2, elastase-1, elastase-2, and cholesterylester lipase. Validation studies found that this transcriptional program also contained products of the endocrine pancreas (Reg-1 and insulin genes) and the expression of the pancreatic transcription factors p48 and PDX-1. By using a LacZ transgene to trace the cellular source of pancreatic gene expression, we found that PDX-1 was expressed in albumin-positive cells that were morphologically indistinguishable from hepatocytes, and in albumin-negative epithelioid cells within zones of pericentral injury. More detailed studies revealed that the mechanisms of heterotopic gene expression in Plg o mice required fibrin(ogen). Collectively, these data reveal a regulatory role for the hemostatic factors plasmin(ogen) and fibrin(ogen) in cellular plasticity within adult tissues of the digestive system. development ͉ differentiation ͉ regeneration

Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation

“…When adult hepatocytes or hepatic progenitor cells are transfected with PDX-1 they gain the ability to synthesize hormones [10][11][12]. Our study thus confirms that adult liver cells maintain a certain plasticity and that liver and pancreas, which arise from adjacent regions of the anterior foregut endoderm [26], recall, in adulthood, similar mechanisms of response to injury [27]. Specifically, here we provide evidence to what was previously hypothesized [28], since we show a de novo, yet endogenous and not virus-mediated, expression of PDX-1 in adult liver cells, namely cholangiocytes.…”

Long-term correction of diabetes in rats after lentiviral hepatic insulin gene therapy

“…Pdx1 is one such master switch gene. In a recent study, liver cells producing pancreatic markers (insulin and PDX1) were induced and localised to areas adjacent to or within injured tissue areas [37]. Lentiviral transduction may represent a cellular insult, making progenitor cells permissive to a pancreatic developmental shift.…”

Urokinase-type plasminogen activator supports liver repair independent of its cellular receptor

“…Based on the observation that liver repair is severely compromised in mice lacking plasminogen (Plg), the Plg family of proteases emerged as key mediators of matrix proteolysis/remodelling following an injury. The hepatic proliferative response is not impeded in Plg-deficient mice following a single administration of hepatotoxin, but the clearance of necrotic foci and the restoration of normal lobular organization are severely impaired within the liver of Plg-deficient mice relative to control animals [6,10,11]. …”