Dopamine Regulates Mobilization of Mesenchymal Stem Cells during Wound Angiogenesis Saurav Shome 1 , Partha Sarathi Dasgupta1*, Sujit Basu2,3,4* 1 Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India, 2 Department of Pathology, Ohio State University, Columbus, Ohio, United States of America, 3 Dorthy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio, United States of America, 4 Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America Abstract Angiogenesis is an important step in the complex biological and molecular events leading to successful healing of dermal wounds. Among the different cellular effectors of wound angiogenesis, the role of mesenchymal stem cells (MSCs) is of current interest due to their transdifferentiation and proangiogenic potentials. Skin is richly innervated by sympathetic nerves which secrete dopamine (DA) and we have recently shown that concentration of DA present in synaptic cleft can significantly inhibit wound tissue neovascularization. As recent reports indicate that MSCs by mobilizing into wound bed play an important role in promoting wound angiogenesis, we therefore investigated the effect of DA on the migration of MSCs in wound tissues. DA acted through its D2 receptors present in the MSCs to inhibit their mobilization to the wound beds by suppressing Akt phosphorylation and actin polymerization. In contrast, this inhibitory effect of DA was reversed after treatment with specific DA D2 receptor antagonist. Increased mobilization of MSCs was demonstrated in the wound site following blockade of DA D2 receptor mediated actions, and this in turn was associated with significantly more angiogenesis in wound tissues. This study is of translational value and indicates use of DA D2 receptor antagonists to stimulate mobilization of these stem cells for faster regeneration of damaged tissues. Citation: Shome S, Dasgupta PS, Basu S (2012) Dopamine Regulates Mobilization of Mesenchymal Stem Cells during Wound Angiogenesis. PLoS ONE 7(2): e31682. doi:10.1371/journal.pone.0031682 Editor: Soumitro Pal, Children’s Hospital Boston & Harvard Medical School, United States of America Received December 20, 2011; Accepted January 15, 2012; Published February 15, 2012 Copyright: 2012 Shome 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. Funding: This study was supported in part by DRDO (Defence Research and Development Organisation, Government of India) Grants DLS/81/48222/LSRB-117/ ID/2006 to Dr. Dasgupta and National Institutes of Health, USA R01-CA124763 to Dr. Basu; CSIR (Council of Scientific and Industrial Research, Government of India) Pre-doctoral Fellowship 9/30(54)/2009-EMR-1 (Dr. Shome). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: partha42002@yahoo.com (PSD); sujit.basu@osumc.edu (SB) Introduction Angiogenesis, the formation of new blood vessels from pre- existing ones is a normal physiological process and plays an important role in wound healing [1–2]. This complex and dynamic process further involves multiple cellular and molecular regulators, among which the roles of endothelial cells [1–2] and endothelial progenitor cells [3–5] have been well documented. However, recent attention has been drawn to the role of mesenchymal stem cells (MSCs) in wound angiogenesis and the healing process [6–10]. MSCs are multipotent stem cells present in adult bone marrow, umbilical vein and adipose tissue, and these adult stem cells have the capacity to proliferate and differentiate into different mesenchymal lineage cells [11–13]. Wound results in the release of various growth factors and cytokines and these molecules by acting as chemokines increase the mobility of MSCs from their sources, thereby facilitating migration of MSCs into the peripheral blood and from there into wound bed [14–16]. Accumulating MSCs at wounded sites accelerate the process of wound tissue angiogenesis, an essential physiological step for successful wound tissue repair by transdifferentiating into different cell types, which include endothelial cells, the principal struc- tural component of wound tissue neovessels [8,10,13,17–19]. In addition, these MSCs have the capacity to release various proangiogenic factors like vascular endothelial growth factor (VEGF) to support the growth, survival and differentiation of endothelial cells [9,13,17,19–20]. Previous studies from our laboratory have conclusively demon- strated that endogenous catecholamine neurotransmitter DA by acting through its D2 receptors can significantly inhibit angiogen- esis in malignant tumors [21–24]. Recent studies from our lab- oratory have also shown that DA by acting via its D2 receptors negatively influences the process of normal wound healing in a murine model of full thickness dermal wounds, and treatment with specific DA D2 receptor antagonist significantly accelerates the process of neovascularization in wound tissues leading to faster healing [25]. As recent reports indicate important roles of MSCs in wound angiogenesis, we therefore investigated whether DA can regulate this neovascularization process in normal wound tissue by influencing the mobilization of MSCs into wound site and their subsequent pro-angiogenic effects during wound healing. Results Treatment with specific DA D2 receptor antagonist following injury significantly increases number of MSCs (CD342 CD452 CD105+ cells) in peripheral blood Recent studies from our laboratory have shown that treatment with specific DA D2 receptor antagonist significantly accelerates the time of wound healing in a murine model of full thickness PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e31682