title: Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats.
abstract: OBJECTIVE
  Highly proliferative fetal liver stem/progenitor cells (FLSPCs) repopulate livers of normal recipients by cell competition. We investigated the mechanisms by which FLSPCs repopulate livers of older compared with younger rats.
  
  
  METHODS
  Fetal liver cells were transplanted from DPPIV(+) F344 rats into DPPIV(-) rats of different ages (2, 6, 14, or 18 months); liver tissues were analyzed 6 months later. Cultured cells and liver tissues were analyzed by reverse transcription polymerase chain reaction, immunoblot, histochemistry, laser-capture microscopy, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling analyses.
  
  
  RESULTS
  We observed 4- to 5-fold increases in liver repopulation when FLSPCs were transplanted into older compared with younger rats. Messenger RNA levels of cyclin-dependent kinase inhibitors increased progressively in livers of older rats; hepatocytes from 20-month-old rats had 6.1-fold higher expression of p15INK4b and were less proliferative in vitro than hepatocytes from 2-month-old rats. Expression of p15INK4b in cultured hepatocytes was up-regulated by activin A, which increased in liver during aging. Activin A inhibited proliferation of adult hepatocytes, whereas FLSPCs were unresponsive because they had reduced expression of activin receptors (eg, ALK-4). In vivo, expanding cell clusters derived from transplanted FLSPCs had lower levels of ALK-4 and p15INK4b and increased levels of Ki-67 compared with the host parenchyma. Liver tissue of older rats had 3-fold more apoptotic cells than that of younger rats.
  
  
  CONCLUSIONS
  FLSPCs, resistant to activin A signaling, repopulate livers of older rats; hepatocytes in older rats have less proliferation because of increased activin A and p15INK4b levels and increased apoptosis than younger rats. These factors and cell types might be manipulated to improve liver cell transplantation strategies in patients with liver diseases in which activin A levels are increased.
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Diseases, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Menthena
authors.forename: Christoph I
authors.initials: CI
authors.lastname: Koehler
authors.forename: Jaswinderpal S
authors.initials: JS
authors.lastname: Sandhu
authors.forename: Mladen I
authors.initials: MI
authors.lastname: Yovchev
authors.forename: Ethel
authors.initials: E
authors.lastname: Hurston
authors.forename: David A
authors.initials: DA
authors.lastname: Shafritz
authors.forename: Michael
authors.initials: M
authors.lastname: Oertel
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics; D053686:Fetal Stem Cells / Q000378:metabolism* / Q000637:transplantation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C493969:Cdkn2b protein, rat; D050762:Cyclin-Dependent Kinase Inhibitor p15; D016213:Cyclins; D019394:Ki-67 Antigen; D012333:RNA, Messenger; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits; D018844:Cyclin-Dependent Kinases; D018819:Dipeptidyl Peptidase 4