Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism

Paul R. Crisostomo, Yue Wang, Troy A. Markel, Meijing Wang, Tim Lahm, Daniel R. Meldrum

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284 Citations (Scopus)

Abstract

Understanding the mechanisms by which adult stem cells produce growth factors may represent an important way to optimize their beneficial paracrine and autocrine effects. Components of the wound milieu may stimulate growth factor production to promote stem cell-mediated repair. We hypothesized that tumor necrosis factor-α (TNF-α), endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF-1), or hepatocyte growth factor (HGF) and that nuclear factor-κB (NFκB), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into four groups (100,000 cells, triplicates) and treated as follows: 1) with vehicle; 2) with stimulant alone [24 h LPS (200 ng/ml), 24 h TNF-α (50 ng/ml), or 24 h hypoxia (1% O2)]; 3) with inhibitor alone [NFκB (PDTC, 1 mM), JNK (TI-JIP, 10 μM), or ERK (ERK Inhibitor II, 25 μM)]; and 4) with stimulant and the various inhibitors. After 24 h incubation, MSC activation was determined by measuring supernatants for VEGF, FGF2, IGF-1, or HGF (ELISA). TNF-α, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production versus controls. Stem cells exposed to injury demonstrated increased activation of NFκB, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NFκB inhibition (50% decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK, and NFκB inhibitor alone did not activate MSC VEGF expression over controls. Various stressors activate human MSCs to increase VEGF, FGF2, HGF, and IGF-1 expression, which depends on an NFkB mechanism.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume294
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

JNK Mitogen-Activated Protein Kinases
Stem cells
Mesenchymal Stromal Cells
Extracellular Signal-Regulated MAP Kinases
Hepatocyte Growth Factor
Intercellular Signaling Peptides and Proteins
Vascular Endothelial Growth Factor A
Tumor Necrosis Factor-alpha
Fibroblast Growth Factor 2
Somatomedins
Stem Cells
Adult Stem Cells
Wounds and Injuries
Chemical activation
Hypoxia
Endotoxins
Production control
Cell growth
Enzyme-Linked Immunosorbent Assay
Repair

Keywords

  • Fibroblast growth factor 2
  • Hepatocyte growth factor
  • Insulin-like growth factor 1
  • Mitogen-activated protein kinase
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

@article{2131b37200a04b7585312ee79609857e,
title = "Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism",
abstract = "Understanding the mechanisms by which adult stem cells produce growth factors may represent an important way to optimize their beneficial paracrine and autocrine effects. Components of the wound milieu may stimulate growth factor production to promote stem cell-mediated repair. We hypothesized that tumor necrosis factor-α (TNF-α), endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF-1), or hepatocyte growth factor (HGF) and that nuclear factor-κB (NFκB), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into four groups (100,000 cells, triplicates) and treated as follows: 1) with vehicle; 2) with stimulant alone [24 h LPS (200 ng/ml), 24 h TNF-α (50 ng/ml), or 24 h hypoxia (1{\%} O2)]; 3) with inhibitor alone [NFκB (PDTC, 1 mM), JNK (TI-JIP, 10 μM), or ERK (ERK Inhibitor II, 25 μM)]; and 4) with stimulant and the various inhibitors. After 24 h incubation, MSC activation was determined by measuring supernatants for VEGF, FGF2, IGF-1, or HGF (ELISA). TNF-α, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production versus controls. Stem cells exposed to injury demonstrated increased activation of NFκB, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NFκB inhibition (50{\%} decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK, and NFκB inhibitor alone did not activate MSC VEGF expression over controls. Various stressors activate human MSCs to increase VEGF, FGF2, HGF, and IGF-1 expression, which depends on an NFkB mechanism.",
keywords = "Fibroblast growth factor 2, Hepatocyte growth factor, Insulin-like growth factor 1, Mitogen-activated protein kinase, Vascular endothelial growth factor",
author = "Crisostomo, {Paul R.} and Yue Wang and Markel, {Troy A.} and Meijing Wang and Tim Lahm and Meldrum, {Daniel R.}",
year = "2008",
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language = "English",
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T1 - Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism

AU - Crisostomo, Paul R.

AU - Wang, Yue

AU - Markel, Troy A.

AU - Wang, Meijing

AU - Lahm, Tim

AU - Meldrum, Daniel R.

PY - 2008/3

Y1 - 2008/3

N2 - Understanding the mechanisms by which adult stem cells produce growth factors may represent an important way to optimize their beneficial paracrine and autocrine effects. Components of the wound milieu may stimulate growth factor production to promote stem cell-mediated repair. We hypothesized that tumor necrosis factor-α (TNF-α), endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF-1), or hepatocyte growth factor (HGF) and that nuclear factor-κB (NFκB), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into four groups (100,000 cells, triplicates) and treated as follows: 1) with vehicle; 2) with stimulant alone [24 h LPS (200 ng/ml), 24 h TNF-α (50 ng/ml), or 24 h hypoxia (1% O2)]; 3) with inhibitor alone [NFκB (PDTC, 1 mM), JNK (TI-JIP, 10 μM), or ERK (ERK Inhibitor II, 25 μM)]; and 4) with stimulant and the various inhibitors. After 24 h incubation, MSC activation was determined by measuring supernatants for VEGF, FGF2, IGF-1, or HGF (ELISA). TNF-α, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production versus controls. Stem cells exposed to injury demonstrated increased activation of NFκB, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NFκB inhibition (50% decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK, and NFκB inhibitor alone did not activate MSC VEGF expression over controls. Various stressors activate human MSCs to increase VEGF, FGF2, HGF, and IGF-1 expression, which depends on an NFkB mechanism.

AB - Understanding the mechanisms by which adult stem cells produce growth factors may represent an important way to optimize their beneficial paracrine and autocrine effects. Components of the wound milieu may stimulate growth factor production to promote stem cell-mediated repair. We hypothesized that tumor necrosis factor-α (TNF-α), endotoxin (LPS), or hypoxia may activate human mesenchymal stem cells (MSCs) to increase release of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), insulin-like growth factor 1 (IGF-1), or hepatocyte growth factor (HGF) and that nuclear factor-κB (NFκB), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) mediates growth factor production from human MSCs. To study this, human MSCs were harvested, passaged, divided into four groups (100,000 cells, triplicates) and treated as follows: 1) with vehicle; 2) with stimulant alone [24 h LPS (200 ng/ml), 24 h TNF-α (50 ng/ml), or 24 h hypoxia (1% O2)]; 3) with inhibitor alone [NFκB (PDTC, 1 mM), JNK (TI-JIP, 10 μM), or ERK (ERK Inhibitor II, 25 μM)]; and 4) with stimulant and the various inhibitors. After 24 h incubation, MSC activation was determined by measuring supernatants for VEGF, FGF2, IGF-1, or HGF (ELISA). TNF-α, LPS, and hypoxia significantly increased human MSC VEGF, FGF2, HGF, and IGF-1 production versus controls. Stem cells exposed to injury demonstrated increased activation of NFκB, ERK, and JNK. VEGF, FGF2, and HGF expression was significantly reduced by NFκB inhibition (50% decrease) but not ERK or JNK inhibition. Moreover, ERK, JNK, and NFκB inhibitor alone did not activate MSC VEGF expression over controls. Various stressors activate human MSCs to increase VEGF, FGF2, HGF, and IGF-1 expression, which depends on an NFkB mechanism.

KW - Fibroblast growth factor 2

KW - Hepatocyte growth factor

KW - Insulin-like growth factor 1

KW - Mitogen-activated protein kinase

KW - Vascular endothelial growth factor

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