alexa Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2 | Abstract
ISSN: 2157-7633

Journal of Stem Cell Research & Therapy
Open Access

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Research Article

Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2

Tino Felka1, Christine Ulrich1, Bernd Rolauffs2, Falk Mittag3, Torsten Kluba3, Peter DeZwart2, Gunnar Ochs2, Michael Bonin4, Kay Nieselt5, Melanie L Hart1,6, Kurt Geckeler7 and Wilhelm K Aicher1,6*
1ZMF Center for Medical Research, University of Tuebingen Medical Faculty, Tuebingen, Germany
2Department of Trauma Surgery, University of Tuebingen, Tuebingen, Germany
3Department of Orthopaedic Surgery, University of Tuebingen Hospital, Tuebingen, Germany
4Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
5Integrative Transcriptomics, Center for Bioinformatics, University of Tuebingen, Tuebingen, Germany
6F6KFO273, Department of Urology, University of Tuebingen Hospital, Tuebingen, Germany
7School of Materials Science and Engineering, Gwangju Institute of Science & Technology (GIST) , 1 Oryong-dong, Buk-gu, Gwangju 500-712 , South Korea
Corresponding Author : Prof. Dr. Wilhelm K. Aicher
KFO273, Department of Urology, University of Tuebingen Hospital (UKT)
Paul-Ehrlich-Str. 15, 72076 Tuebingen, Germany
Tel: +49 7071 298 7020
Fax: +49 7071 292 5072
E-mail: [email protected]
Received February 21, 2014; Accepted April 12, 2014; Published April 14, 2014
Citation: Felka T, Ulrich C, Rolauffs B, Mittag F, Kluba T, et al. (2014) Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2. J Stem Cell Res Ther 4:195. doi:10.4172/2157-7633.1000195
Copyright: © 2014 Felka T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Mesenchymal stromal cells (MSC) are a promising therapy for wound healing and regeneration of inflamed tissues. They are used clinically for different symptoms and diseases and are being investigated in clinical trials world wide at an increasing rate. However, depending on the application protocol and site of treatment, MSC may face an inflammatory environment. Objective: Nitric oxide (NO) is one of the soluble factors produced in acute and chronic inflammation and influences growth, apoptosis, proliferation and differentiation of cells. NO therefore my have an influence on MSC injected into inflamed sites. Thus we investigated the effects of NO radicals on human MSC. Methods: Human MSC were expanded and characterized. Expression of the mesenchymal linage markers was determined by flow cytometry and their tri-lineage differentiation was explored in vitro. MSC were incubated with the NO-donor sodium nitroprusside (SNP) at different concentrations (5 μM-5 mM) and over different periods of time (15 min–24 hrs), and analyzed for their respiratory activity, gene expression responses, cell signalling pathways, and differentiation potential. Results: Human MSC expressed the mesenchymal marker proteins CD73, CD90, CD105, CD146, but failed to express the hematopoietic markers CD11b, CD14, CD34, and CD45. Activation of the MSC in vitro by nitric oxide activated c-Raf-, p-38-MAPK, and p-JNK- mediated signalling in a dose dependent manner, and also significantly regulated genes involved in cellular proliferation (cyclin D1, GAS1), apoptotis (p53), and induced an intense nuclear factor E2-related factor (NRF2)-associated stress response. Moreover, NO inhibited the entry of MSC in the osteogenic differentiation pathway and NO-treated MSC expressed less of the transcription factor Runx2. In contrast, the expression of the adipogenic marker gene PPARγ2 remained unchanged. Conclusion: We conclude that NO modulates the metabolism of MSC and compromises their osteogenic differentiation potential, which may have detrimental consequences for bone remodelling or bone regeneration.

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