The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis

Liping Liu, Govardhana Rao Yannam, Taichiro Nishikawa, Toshiyuki Yamamoto, Hesham Basma, Ryotaro Ito, Masaki Nagaya, Joyeeta Dutta-Moscato, Donna B. Stolz, Fenghai Duan, Klaus H. Kaestner, Yoram Vodovotz, Alejandro Soto-Gutierrez, Ira J. Fox

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

In advanced cirrhosis, impaired function is caused by intrinsic damage to the native liver cells and from the abnormal microenvironment in which the cells reside. The extent to which each plays a role in liver failure and regeneration is unknown. To examine this issue, hepatocytes from cirrhotic and age-matched control rats were isolated, characterized, and transplanted into the livers of noncirrhotic hosts whose livers permit extensive repopulation with donor cells. Primary hepatocytes derived from livers with advanced cirrhosis and compensated function maintained metabolic activity and the ability to secrete liver-specific proteins, whereas hepatocytes derived from cirrhotic livers with decompensated function failed to maintain metabolic or secretory activity. Telomere studies and transcriptomic analysis of hepatocytes recovered from progressively worsening cirrhotic livers suggest that hepatocytes from irreversibly failing livers show signs of replicative senescence and express genes that simultaneously drive both proliferation and apoptosis, with a later effect on metabolism, all under the control of a central cluster of regulatory genes, including nuclear factor κB and hepatocyte nuclear factor 4α. Cells from cirrhotic and control livers engrafted equally well, but those from animals with cirrhosis and failing livers showed little initial evidence of proliferative capacity or function. Both, however, recovered more than 2 months after transplantation, indicating that either mature hepatocytes or a subpopulation of adult stem cells are capable of full recovery in severe cirrhosis. Conclusion: Transplantation studies indicate that the state of the host microenvironment is critical to the regenerative potential of hepatocytes, and that a change in the extracellular matrix can lead to regeneration and restoration of function by cells derived from livers with end-stage organ failure.

Original languageEnglish (US)
Pages (from-to)1529-1539
Number of pages11
JournalHepatology
Volume55
Issue number5
DOIs
StatePublished - May 1 2012

Fingerprint

Regeneration
Hepatocytes
Fibrosis
Liver
Hepatocyte Nuclear Factor 4
Transplantation
Cellular Microenvironment
Adult Stem Cells
Liver Regeneration
Cell Aging
Telomere
Liver Failure
Regulator Genes
Liver Cirrhosis
Extracellular Matrix
Apoptosis
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

Liu, L., Yannam, G. R., Nishikawa, T., Yamamoto, T., Basma, H., Ito, R., ... Fox, I. J. (2012). The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis. Hepatology, 55(5), 1529-1539. https://doi.org/10.1002/hep.24815

The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis. / Liu, Liping; Yannam, Govardhana Rao; Nishikawa, Taichiro; Yamamoto, Toshiyuki; Basma, Hesham; Ito, Ryotaro; Nagaya, Masaki; Dutta-Moscato, Joyeeta; Stolz, Donna B.; Duan, Fenghai; Kaestner, Klaus H.; Vodovotz, Yoram; Soto-Gutierrez, Alejandro; Fox, Ira J.

In: Hepatology, Vol. 55, No. 5, 01.05.2012, p. 1529-1539.

Research output: Contribution to journalArticle

Liu, L, Yannam, GR, Nishikawa, T, Yamamoto, T, Basma, H, Ito, R, Nagaya, M, Dutta-Moscato, J, Stolz, DB, Duan, F, Kaestner, KH, Vodovotz, Y, Soto-Gutierrez, A & Fox, IJ 2012, 'The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis', Hepatology, vol. 55, no. 5, pp. 1529-1539. https://doi.org/10.1002/hep.24815
Liu, Liping ; Yannam, Govardhana Rao ; Nishikawa, Taichiro ; Yamamoto, Toshiyuki ; Basma, Hesham ; Ito, Ryotaro ; Nagaya, Masaki ; Dutta-Moscato, Joyeeta ; Stolz, Donna B. ; Duan, Fenghai ; Kaestner, Klaus H. ; Vodovotz, Yoram ; Soto-Gutierrez, Alejandro ; Fox, Ira J. / The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis. In: Hepatology. 2012 ; Vol. 55, No. 5. pp. 1529-1539.
@article{3fb9603a9b5045738328faf3a719229c,
title = "The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis",
abstract = "In advanced cirrhosis, impaired function is caused by intrinsic damage to the native liver cells and from the abnormal microenvironment in which the cells reside. The extent to which each plays a role in liver failure and regeneration is unknown. To examine this issue, hepatocytes from cirrhotic and age-matched control rats were isolated, characterized, and transplanted into the livers of noncirrhotic hosts whose livers permit extensive repopulation with donor cells. Primary hepatocytes derived from livers with advanced cirrhosis and compensated function maintained metabolic activity and the ability to secrete liver-specific proteins, whereas hepatocytes derived from cirrhotic livers with decompensated function failed to maintain metabolic or secretory activity. Telomere studies and transcriptomic analysis of hepatocytes recovered from progressively worsening cirrhotic livers suggest that hepatocytes from irreversibly failing livers show signs of replicative senescence and express genes that simultaneously drive both proliferation and apoptosis, with a later effect on metabolism, all under the control of a central cluster of regulatory genes, including nuclear factor κB and hepatocyte nuclear factor 4α. Cells from cirrhotic and control livers engrafted equally well, but those from animals with cirrhosis and failing livers showed little initial evidence of proliferative capacity or function. Both, however, recovered more than 2 months after transplantation, indicating that either mature hepatocytes or a subpopulation of adult stem cells are capable of full recovery in severe cirrhosis. Conclusion: Transplantation studies indicate that the state of the host microenvironment is critical to the regenerative potential of hepatocytes, and that a change in the extracellular matrix can lead to regeneration and restoration of function by cells derived from livers with end-stage organ failure.",
author = "Liping Liu and Yannam, {Govardhana Rao} and Taichiro Nishikawa and Toshiyuki Yamamoto and Hesham Basma and Ryotaro Ito and Masaki Nagaya and Joyeeta Dutta-Moscato and Stolz, {Donna B.} and Fenghai Duan and Kaestner, {Klaus H.} and Yoram Vodovotz and Alejandro Soto-Gutierrez and Fox, {Ira J.}",
year = "2012",
month = "5",
day = "1",
doi = "10.1002/hep.24815",
language = "English (US)",
volume = "55",
pages = "1529--1539",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis

AU - Liu, Liping

AU - Yannam, Govardhana Rao

AU - Nishikawa, Taichiro

AU - Yamamoto, Toshiyuki

AU - Basma, Hesham

AU - Ito, Ryotaro

AU - Nagaya, Masaki

AU - Dutta-Moscato, Joyeeta

AU - Stolz, Donna B.

AU - Duan, Fenghai

AU - Kaestner, Klaus H.

AU - Vodovotz, Yoram

AU - Soto-Gutierrez, Alejandro

AU - Fox, Ira J.

PY - 2012/5/1

Y1 - 2012/5/1

N2 - In advanced cirrhosis, impaired function is caused by intrinsic damage to the native liver cells and from the abnormal microenvironment in which the cells reside. The extent to which each plays a role in liver failure and regeneration is unknown. To examine this issue, hepatocytes from cirrhotic and age-matched control rats were isolated, characterized, and transplanted into the livers of noncirrhotic hosts whose livers permit extensive repopulation with donor cells. Primary hepatocytes derived from livers with advanced cirrhosis and compensated function maintained metabolic activity and the ability to secrete liver-specific proteins, whereas hepatocytes derived from cirrhotic livers with decompensated function failed to maintain metabolic or secretory activity. Telomere studies and transcriptomic analysis of hepatocytes recovered from progressively worsening cirrhotic livers suggest that hepatocytes from irreversibly failing livers show signs of replicative senescence and express genes that simultaneously drive both proliferation and apoptosis, with a later effect on metabolism, all under the control of a central cluster of regulatory genes, including nuclear factor κB and hepatocyte nuclear factor 4α. Cells from cirrhotic and control livers engrafted equally well, but those from animals with cirrhosis and failing livers showed little initial evidence of proliferative capacity or function. Both, however, recovered more than 2 months after transplantation, indicating that either mature hepatocytes or a subpopulation of adult stem cells are capable of full recovery in severe cirrhosis. Conclusion: Transplantation studies indicate that the state of the host microenvironment is critical to the regenerative potential of hepatocytes, and that a change in the extracellular matrix can lead to regeneration and restoration of function by cells derived from livers with end-stage organ failure.

AB - In advanced cirrhosis, impaired function is caused by intrinsic damage to the native liver cells and from the abnormal microenvironment in which the cells reside. The extent to which each plays a role in liver failure and regeneration is unknown. To examine this issue, hepatocytes from cirrhotic and age-matched control rats were isolated, characterized, and transplanted into the livers of noncirrhotic hosts whose livers permit extensive repopulation with donor cells. Primary hepatocytes derived from livers with advanced cirrhosis and compensated function maintained metabolic activity and the ability to secrete liver-specific proteins, whereas hepatocytes derived from cirrhotic livers with decompensated function failed to maintain metabolic or secretory activity. Telomere studies and transcriptomic analysis of hepatocytes recovered from progressively worsening cirrhotic livers suggest that hepatocytes from irreversibly failing livers show signs of replicative senescence and express genes that simultaneously drive both proliferation and apoptosis, with a later effect on metabolism, all under the control of a central cluster of regulatory genes, including nuclear factor κB and hepatocyte nuclear factor 4α. Cells from cirrhotic and control livers engrafted equally well, but those from animals with cirrhosis and failing livers showed little initial evidence of proliferative capacity or function. Both, however, recovered more than 2 months after transplantation, indicating that either mature hepatocytes or a subpopulation of adult stem cells are capable of full recovery in severe cirrhosis. Conclusion: Transplantation studies indicate that the state of the host microenvironment is critical to the regenerative potential of hepatocytes, and that a change in the extracellular matrix can lead to regeneration and restoration of function by cells derived from livers with end-stage organ failure.

UR - http://www.scopus.com/inward/record.url?scp=84859988520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859988520&partnerID=8YFLogxK

U2 - 10.1002/hep.24815

DO - 10.1002/hep.24815

M3 - Article

C2 - 22109844

AN - SCOPUS:84859988520

VL - 55

SP - 1529

EP - 1539

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 5

ER -