TGF-α increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms

Yue Wang, Paul R. Crisostomo, Meijing Wang, Troy A. Markel, Nathan M. Novotny, Daniel R. Meldrum

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Transforming growth factor-α (TGF-α) may be an important mediator of wound healing and the injury response. Human bone marrow mesenchymal stem cells (MSCs) release VEGF as a potentially beneficial paracrine response; however, it remains unknown whether TGF-α stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF-α would increase human MSC VEGF production by MAP kinase kinase (MAPKK/MEK), phosphatidylinositol 3-kinase (PI3-K)-, ERK, and JNK-dependent mechanisms. To study this, MSCs were cultured and divided into the following groups: 1) with vehicle; 2) with various stimulants alone: TGF-α, TNF-α, or TGF-α+TNF-α; 3) with individual kinase inhibitors alone (two different inhibitors for each of the following kinases: MEK, PI3-K, ERK, or JNK); and 4) with the above stimulants and each of the eight inhibitors. After 24-h incubation, a TGF-α dose-response curve demonstrated that low-dose TGF-α (500 pg/ml) suppressed MSC production of VEGF compared with vehicle (502 ± 16 pg/105 cells/ml to 332 ± 9 pg/105 cells/ml), while high-dose TGF-α (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/105 cells/ml). High-dose TGF-α also increased TNF-α-stimulated release of VEGF from MSCs. MSCs exposed to TGF-α and/or TNF-α also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF-α-stimulated production of VEGF by MSCs and the additive effect of TNF-α and TGF-α on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF-α increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 2008

Fingerprint

Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinase Kinases
Transforming Growth Factors
Mesenchymal Stromal Cells
Vascular Endothelial Growth Factor A
MAP Kinase Kinase Kinases
Wound Healing

Keywords

  • Cellular therapy
  • Growth factor
  • Human mesenchymal stem cells
  • MAPK

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

TGF-α increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms. / Wang, Yue; Crisostomo, Paul R.; Wang, Meijing; Markel, Troy A.; Novotny, Nathan M.; Meldrum, Daniel R.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 295, No. 4, 10.2008.

Research output: Contribution to journalArticle

@article{38074c3a3ae5479ab311f984f24a91f9,
title = "TGF-α increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms",
abstract = "Transforming growth factor-α (TGF-α) may be an important mediator of wound healing and the injury response. Human bone marrow mesenchymal stem cells (MSCs) release VEGF as a potentially beneficial paracrine response; however, it remains unknown whether TGF-α stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF-α would increase human MSC VEGF production by MAP kinase kinase (MAPKK/MEK), phosphatidylinositol 3-kinase (PI3-K)-, ERK, and JNK-dependent mechanisms. To study this, MSCs were cultured and divided into the following groups: 1) with vehicle; 2) with various stimulants alone: TGF-α, TNF-α, or TGF-α+TNF-α; 3) with individual kinase inhibitors alone (two different inhibitors for each of the following kinases: MEK, PI3-K, ERK, or JNK); and 4) with the above stimulants and each of the eight inhibitors. After 24-h incubation, a TGF-α dose-response curve demonstrated that low-dose TGF-α (500 pg/ml) suppressed MSC production of VEGF compared with vehicle (502 ± 16 pg/105 cells/ml to 332 ± 9 pg/105 cells/ml), while high-dose TGF-α (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/105 cells/ml). High-dose TGF-α also increased TNF-α-stimulated release of VEGF from MSCs. MSCs exposed to TGF-α and/or TNF-α also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF-α-stimulated production of VEGF by MSCs and the additive effect of TNF-α and TGF-α on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF-α increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.",
keywords = "Cellular therapy, Growth factor, Human mesenchymal stem cells, MAPK",
author = "Yue Wang and Crisostomo, {Paul R.} and Meijing Wang and Markel, {Troy A.} and Novotny, {Nathan M.} and Meldrum, {Daniel R.}",
year = "2008",
month = "10",
doi = "10.1152/ajpregu.90383.2008",
language = "English",
volume = "295",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - TGF-α increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms

AU - Wang, Yue

AU - Crisostomo, Paul R.

AU - Wang, Meijing

AU - Markel, Troy A.

AU - Novotny, Nathan M.

AU - Meldrum, Daniel R.

PY - 2008/10

Y1 - 2008/10

N2 - Transforming growth factor-α (TGF-α) may be an important mediator of wound healing and the injury response. Human bone marrow mesenchymal stem cells (MSCs) release VEGF as a potentially beneficial paracrine response; however, it remains unknown whether TGF-α stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF-α would increase human MSC VEGF production by MAP kinase kinase (MAPKK/MEK), phosphatidylinositol 3-kinase (PI3-K)-, ERK, and JNK-dependent mechanisms. To study this, MSCs were cultured and divided into the following groups: 1) with vehicle; 2) with various stimulants alone: TGF-α, TNF-α, or TGF-α+TNF-α; 3) with individual kinase inhibitors alone (two different inhibitors for each of the following kinases: MEK, PI3-K, ERK, or JNK); and 4) with the above stimulants and each of the eight inhibitors. After 24-h incubation, a TGF-α dose-response curve demonstrated that low-dose TGF-α (500 pg/ml) suppressed MSC production of VEGF compared with vehicle (502 ± 16 pg/105 cells/ml to 332 ± 9 pg/105 cells/ml), while high-dose TGF-α (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/105 cells/ml). High-dose TGF-α also increased TNF-α-stimulated release of VEGF from MSCs. MSCs exposed to TGF-α and/or TNF-α also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF-α-stimulated production of VEGF by MSCs and the additive effect of TNF-α and TGF-α on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF-α increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.

AB - Transforming growth factor-α (TGF-α) may be an important mediator of wound healing and the injury response. Human bone marrow mesenchymal stem cells (MSCs) release VEGF as a potentially beneficial paracrine response; however, it remains unknown whether TGF-α stimulates the production of VEGF from MSCs and, if so, by which mechanisms. We hypothesized that TGF-α would increase human MSC VEGF production by MAP kinase kinase (MAPKK/MEK), phosphatidylinositol 3-kinase (PI3-K)-, ERK, and JNK-dependent mechanisms. To study this, MSCs were cultured and divided into the following groups: 1) with vehicle; 2) with various stimulants alone: TGF-α, TNF-α, or TGF-α+TNF-α; 3) with individual kinase inhibitors alone (two different inhibitors for each of the following kinases: MEK, PI3-K, ERK, or JNK); and 4) with the above stimulants and each of the eight inhibitors. After 24-h incubation, a TGF-α dose-response curve demonstrated that low-dose TGF-α (500 pg/ml) suppressed MSC production of VEGF compared with vehicle (502 ± 16 pg/105 cells/ml to 332 ± 9 pg/105 cells/ml), while high-dose TGF-α (250 ng/ml) significantly increased MSC VEGF production (603 ± 24 pg/105 cells/ml). High-dose TGF-α also increased TNF-α-stimulated release of VEGF from MSCs. MSCs exposed to TGF-α and/or TNF-α also demonstrated increased activation of PI3-K, JNK, and ERK. The TGF-α-stimulated production of VEGF by MSCs and the additive effect of TNF-α and TGF-α on VEGF production were abolished by MEK and PI3-K inhibition, but not ERK or JNK inhibition. Our data suggest that TGF-α increases VEGF production in MSCs via MEK- and PI3-K- but not ERK- or JNK-dependent mechanisms.

KW - Cellular therapy

KW - Growth factor

KW - Human mesenchymal stem cells

KW - MAPK

UR - http://www.scopus.com/inward/record.url?scp=57349153021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57349153021&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.90383.2008

DO - 10.1152/ajpregu.90383.2008

M3 - Article

C2 - 18685072

AN - SCOPUS:57349153021

VL - 295

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 4

ER -