Original articlePlatelet derived bFGF mediates vascular integrative mechanisms of mesenchymal stem cells in vitro
Introduction
Chronic and acute heart failure is the major cause of morbidity and mortality in non-fatal myocardial infarction. Several substances have been successfully established for the treatment of heart failure over the last decades including beta-blockers, ACE-inhibitors or aldosteron antagonists. However, further therapeutic modalities are urgently needed to reduce complications of heart failure resulting from coronary heart disease, myocarditis or cardiomyopathy.
Multipotent mesenchymal stromal cells (MSC), which comprise a rare population (between 0.01% and 0.02%) in human bone marrow (BM) [1], are able to differentiate into cell types of endodermal, ectodermal and mesodermal origin [2]. Recently, MSCs have been shown to differentiate to cardiomyocytes [3]. In a rat model of myocardial infarction, transplanted MSCs were able to restore cardiac function 4 weeks after induction of ischemia [4]. Moreover, other studies suggested an implication of mesenchymal stem cells for the restoration of vessel integrity at sites of vascular lesions [5]. At sites of disrupted endothelium, platelets rapidly adhere to the subendothelium, thereby initially cover the defect and initiate the healing process [6]. Recently, we could identify one of the regeneration mechanisms initiated by platelets. Platelets recruited circulating progenitor cells to exposed collagen and induced a differentiation into mature endothelial cells [7], [8], [9]. Wang et al. were able to show that the number of circulating MSCs is substantially altered during myocardial infarction [10]. Given the potential of MSCs to differentiate into cardiomyocytes and endothelial cells, MSCs have been proposed to be a promising therapeutic option for the treatment of myocardial pathologies in regenerative medicine [11]. However, the mechanisms regulating the recruitment of MSCs to the endothelium are poorly understood so far. Similarly to CD34+ hematopoietic stem cells human MSCs interact at high shear conditions with the vessel wall in a highly coordinated adhesion cascade involving selectins and integrins [12], [13]. Based on this and our previous results that platelets can enhance homing and biologic functions of stem cells [7], [8], [14], [15] we hypothesized that platelets recruit MSCs to the endothelium and induce MSCs to participate in the restoration of vascular integrity after endothelial injury.
Section snippets
Reagents
Monoclonal antibody (mAb) anti-human basic fibroblast growth factor (bFGF, clone FB-8) was bought from Sigma-Aldrich Chemie GmbH (Steinheim, Germany), mAb anti-human PDGF from R&D Systems, mAb anti-human CD51 (clone AMF7) and anti-CD11b (clone Bear1) from Immunotech (Marseille, France), mAb anti-αvβ3 (clone LM609), from Chemicon International (Temecula, CA), MAb anti-CD49d (clone 9F10), from BD Bioscience (Bedford, MA). Recombinant human IL-1β and recombinant human TNF-alpha was from Tebu-Bio
Platelets mediate the adhesion of MSCs to endothelial cells under arterial shear conditions
Recently, we were able to show that platelets represent a central adhesion mediator of mouse and human circulating stem cells to exposed collagen and vascular lesions [7], [8]. To address, whether platelets may also direct MSCs to the endothelium, primary human arterial endothelial cells were immobilized and exposed to platelets or IL-1β. Interestingly, in this setting adhesion of MSCs to endothelial cells under platelet influence was significantly (p < 0.05) increased compared to untreated
Discussion
Mesenchymal stem cells (MSCs) are pluripotent adult stem cells residing within the bone marrow, which have been shown to differentiate to endothelial cells and smooth muscle cells [3], [4], [30]. MSCs, which can be mobilized during myocardial infarction and fluctuate in terms of numbers within the circulation, are referred to as potential regenerative effector cells in ischemic heart disease [10], [30]. The mechanisms, how MSCs reach the infarct related area, however, are incompletely
Acknowledgments
We acknowledge the excellent technical assistance of Iris Schäfer and Heike Runge.
The study was supported by grants of the Deutsche Forschungsgemeinschaft (Graduiertenkolleg GK794, MA121/2-1, Li849/3-1), the Wilhelm Sander-Stiftung (Nr. 2003.0601), the Novartis-Stiftung, the Karl & Lore Klein Stiftung (D.30.08886), the Karl Kuhn Stiftung (AZ III 1.7-0415.221.18-01/AE04/2005), the Bundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie and the fortuene program of the UKT. Dr.
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