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

Kumar Shanmukhappa, Reena Mourya, Gregg E. Sabla, Jay L. Degen, Jorge A. Bezerra

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 Pig-deficient (Plg°) 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 PIg/fibrinogen system. To this end, we generated biotinylated cRNA pools from livers of Plg° 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° 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 expres-sion in Plg° 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.

Original languageEnglish (US)
Pages (from-to)10182-10187
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - Jul 19 2005
Externally publishedYes


  • Development
  • Differentiation
  • Regeneration

ASJC Scopus subject areas

  • General


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