Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice.
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 Plg/fibrinogen 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 cholesteryl-ester 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.
Shanmukhappa
Kumar
K
Division of Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
Mourya
Reena
R
Sabla
Gregg E
GE
Degen
Jay L
JL
Bezerra
Jorge A
JA
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008049:Lipase / Q000378:metabolism; D051847:Lithostathine; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D014362:Trypsinogen / Q000378:metabolism
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494228:Isgf3g protein, mouse; D051847:Lithostathine; D009419:Nerve Tissue Proteins; C497615:Reg1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D005340:Fibrinogen; D010958:Plasminogen; D014362:Trypsinogen; D002251:Carbon Tetrachloride; D008049:Lipase; D000681:Amylases; D010196:Pancreatic Elastase