Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats.
| Title: | Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats. |
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| Authors: | Menthena A; 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.; Koehler CI; Sandhu JS; Yovchev MI; Hurston E; Shafritz DA; Oertel M |
| Source: | Gastroenterology [Gastroenterology] 2011 Mar; Vol. 140 (3), pp. 1009-20. Date of Electronic Publication: 2010 Dec 11. |
| Publication Type: | Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE |
| Imprint Name(s): | Publication: Philadelphia, PA : W.B. Saunders; Original Publication: Baltimore. |
| MeSH Terms: | Cell Proliferation* ; Liver Regeneration* ; Signal Transduction*; Aging/*metabolism ; Cyclin-Dependent Kinase Inhibitor p15/*metabolism ; Fetal Stem Cells/*metabolism ; Inhibin-beta Subunits/*metabolism ; Liver/*metabolism; Aging/pathology ; Cyclin-Dependent Kinase Inhibitor p15/genetics ; Cyclin-Dependent Kinases/metabolism ; Cyclins/metabolism ; Dipeptidyl Peptidase 4/deficiency ; Dipeptidyl Peptidase 4/genetics ; Fetal Stem Cells/transplantation ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Inhibin-beta Subunits/genetics ; Ki-67 Antigen/metabolism ; Liver/embryology ; Liver/pathology ; RNA, Messenger/metabolism ; Age Factors ; Animals ; Apoptosis ; Blotting, Western ; Cells, Cultured ; Immunohistochemistry ; In Situ Nick-End Labeling ; Rats ; Rats, Inbred F344 ; Rats, Transgenic ; Reverse Transcriptase Polymerase Chain Reaction |
| Abstract: | Background & Aims: 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.; (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.) |
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| Grant Information: | P30 DK041296 United States DK NIDDK NIH HHS; R01 DK017609 United States DK NIDDK NIH HHS; P30 DK41296 United States DK NIDDK NIH HHS; R01 DK17609 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 0 (Cdkn2b protein, rat); 0 (Cyclin-Dependent Kinase Inhibitor p15); 0 (Cyclins); 0 (Ki-67 Antigen); 0 (RNA, Messenger); 0 (inhibin beta A subunit); 93443-12-0 (Inhibin-beta Subunits); EC 2.7.11.22 (Cyclin-Dependent Kinases); EC 3.4.14.5 (Dipeptidyl Peptidase 4) |
| Entry Date(s): | Date Created: 20101215 Date Completed: 20110509 Latest Revision: 20250529 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3087123 |
| DOI: | 10.1053/j.gastro.2010.12.003 |
| PMID: | 21147108 |
| Database: | MEDLINE |
Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't