Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure

Hiroshi Yagi, Biju Parekkadan, Kazuhiro Suganuma, Alejandro Soto-Gutierrez, Ronald G. Tompkins, Arno W. Tilles, Martin L. Yarmush

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF.

Original languageEnglish
Pages (from-to)3377-3388
Number of pages12
JournalTissue Engineering - Part A
Volume15
Issue number11
DOIs
Publication statusPublished - 2009 Nov 1

Fingerprint

Acute Liver Failure
Stem cells
Mesenchymal Stromal Cells
Liver
Hepatocytes
Stem Cells
Equipment and Supplies
Coculture Techniques
Serum
Therapeutics
Acute-Phase Reaction
Therapeutic Uses
Cell death
Anti-Inflammatory Agents
Apoptosis
Rats
Cytokines
Technology
Modulation
Molecules

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomedical Engineering
  • Biomaterials

Cite this

Yagi, H., Parekkadan, B., Suganuma, K., Soto-Gutierrez, A., Tompkins, R. G., Tilles, A. W., & Yarmush, M. L. (2009). Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. Tissue Engineering - Part A, 15(11), 3377-3388. https://doi.org/10.1089/ten.tea.2008.0681

Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. / Yagi, Hiroshi; Parekkadan, Biju; Suganuma, Kazuhiro; Soto-Gutierrez, Alejandro; Tompkins, Ronald G.; Tilles, Arno W.; Yarmush, Martin L.

In: Tissue Engineering - Part A, Vol. 15, No. 11, 01.11.2009, p. 3377-3388.

Research output: Contribution to journalArticle

Yagi, H, Parekkadan, B, Suganuma, K, Soto-Gutierrez, A, Tompkins, RG, Tilles, AW & Yarmush, ML 2009, 'Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure', Tissue Engineering - Part A, vol. 15, no. 11, pp. 3377-3388. https://doi.org/10.1089/ten.tea.2008.0681
Yagi, Hiroshi ; Parekkadan, Biju ; Suganuma, Kazuhiro ; Soto-Gutierrez, Alejandro ; Tompkins, Ronald G. ; Tilles, Arno W. ; Yarmush, Martin L. / Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. In: Tissue Engineering - Part A. 2009 ; Vol. 15, No. 11. pp. 3377-3388.
@article{ba1bdafa18e04c2683fcbdf5e067fed8,
title = "Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure",
abstract = "Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF.",
author = "Hiroshi Yagi and Biju Parekkadan and Kazuhiro Suganuma and Alejandro Soto-Gutierrez and Tompkins, {Ronald G.} and Tilles, {Arno W.} and Yarmush, {Martin L.}",
year = "2009",
month = "11",
day = "1",
doi = "10.1089/ten.tea.2008.0681",
language = "English",
volume = "15",
pages = "3377--3388",
journal = "Tissue Engineering - Part A",
issn = "1937-3341",
publisher = "Mary Ann Liebert Inc.",
number = "11",

}

TY - JOUR

T1 - Long-term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure

AU - Yagi, Hiroshi

AU - Parekkadan, Biju

AU - Suganuma, Kazuhiro

AU - Soto-Gutierrez, Alejandro

AU - Tompkins, Ronald G.

AU - Tilles, Arno W.

AU - Yarmush, Martin L.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF.

AB - Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF.

UR - http://www.scopus.com/inward/record.url?scp=72649101116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72649101116&partnerID=8YFLogxK

U2 - 10.1089/ten.tea.2008.0681

DO - 10.1089/ten.tea.2008.0681

M3 - Article

C2 - 19397469

AN - SCOPUS:72649101116

VL - 15

SP - 3377

EP - 3388

JO - Tissue Engineering - Part A

JF - Tissue Engineering - Part A

SN - 1937-3341

IS - 11

ER -