Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection

Jeremy L. Herrmann, Yue Wang, Aaron M. Abarbanell, Brent R. Weil, Jiangning Tan, Daniel R. Meldrum

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Mesenchymal stem cells (MSCs) are a promising therapy for acute organ ischemia in part due to their paracrine production of growth factors. However, transplanted cells encounter an inflammatory environment that mitigates their function and survival, and treating the cells with exogenous agents during ex vivo expansion before transplantation is one strategy for overcoming this limitation by enhancing paracrine function. We hypothesized that preconditioning bone marrow MSCs with TGF-α would 1) increase MSC production of the critical paracrine factor, vascular endothelial growth factor (VEGF), via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism and 2) enhance myocardial functional recovery in a rat model of acute myocardial I/R injury. To study this, bone marrow MSCs were harvested from adult male mice (C57BL/6J) and treated in vitro for 24 h according to the following groups: 1) control, 2) TGF-α (250 ng mL -1), 3) TNF-α (50 ng mL), 4) TGF-α + TNF-α, 5) hypoxia, and 6) TGF-α + hypoxia. For the isolated heart perfusion experiments, adult male Sprague-Dawley rat hearts were isolated, perfused via the Langendorff model, and subjected to I/R. Vehicle or MSCs with or without TGF-α preconditioning were infused immediately before ischemia. Mesenchymal stem cells were also treated with TGF-α alone or in combination with a p38 MAPK inhibitor (SB202190). In vitro, TGF-α increased MSC VEGF production alone (157.9 ± 1.11 - 291.0 ± 3.74 pg 10 -5; P <0.05) and, to a greater extent, in combination with TNF-α or hypoxia (364.5 ± 0.868 and 342.0 ± 7.92 pg 10 -5 cells, respectively; P <0.05 vs. TGF-α alone). Postischemic myocardial functional recovery was greater in hearts infused with TGF-α-preconditioned MSCs compared with untreated MSCs or vehicle. Myocardial IL-1β and TNF-α production and activation of caspase 3 were significantly decreased after infusion of both cell groups. p38 MAPK inhibition suppressed TGF-α-stimulated MSC VEGF production and postischemic myocardial recovery. These results suggest that TGF-α stimulates MSC VEGF production in part via a p38 MAPK-dependent mechanism, and preconditioning MSCs with TGF-α may enhance their ability to protect myocardium during I/R injury.

Original languageEnglish (US)
Pages (from-to)24-30
Number of pages7
JournalShock
Volume33
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Fingerprint

Transforming Growth Factor alpha
Mesenchymal Stromal Cells
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Ischemia
Bone Marrow
Wounds and Injuries
Protein Kinase Inhibitors
Interleukin-1
Inbred C57BL Mouse
Caspase 3
Sprague Dawley Rats
Cell Survival
Intercellular Signaling Peptides and Proteins
Myocardium
Perfusion
Transplantation

Keywords

  • I/R injury
  • Inflammation
  • Isolated heart perfusion
  • Myocardial ischemia
  • Stem cell therapy

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this

Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection. / Herrmann, Jeremy L.; Wang, Yue; Abarbanell, Aaron M.; Weil, Brent R.; Tan, Jiangning; Meldrum, Daniel R.

In: Shock, Vol. 33, No. 1, 01.2010, p. 24-30.

Research output: Contribution to journalArticle

Herrmann, Jeremy L. ; Wang, Yue ; Abarbanell, Aaron M. ; Weil, Brent R. ; Tan, Jiangning ; Meldrum, Daniel R. / Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection. In: Shock. 2010 ; Vol. 33, No. 1. pp. 24-30.
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