Recent reports that HSCs can regenerate infarcted myocardium have unleashed a tidal wave of enthusiasm for translating these findings to the clinical arena. A number of institutions have already initiated studies of cytokine or HSC therapy in patients with acute MI. It is our opinion that this rush to clinical trials is not only premature but possibly counterproductive, and that further, careful preclinical investigation is necessary to establish the efficacy of various treatment protocols and the underlying mechanisms. For example, nothing is currently known regarding whether i.v. HSC administration is effective, which cytokine or combination of cytokines is more likely to succeed, how long the window of efficacy is, and whether HSCs are effective in the context of reperfusion. Similarly, nothing is known regarding the nature of the integrin/adhesion molecule interactions that underlie the homing of HSCs or the potential synergistic role of accessory calls, specifically, the FCs. Our fundamental hypothesis is that both i.v. injected and cytokine-mobilized HSCs can regenerate infarcted myocardium and that this process is mediated by a well-defined cascade of molecular interactions that involve specific adhesion molecules (ICAM-1, VCAM-1, P-selectin, and E-selectin), integrins (VLA-4, VLA-5, and LFA-1), chemokines (SDF-1), and chemokine receptors (CXCR-4). We further propose that FCs exert an important potentiating effect on HSC-dependent cardiac reqeneration and that this process can be further enhanced by FL These hypotheses will be tested in a well-established murine model using a broad multidisciplinary approach that will encompass diverse techniques (integrative physiology, protein chemistry, biochemistry, pathology, confocal microscopy, immunohistochemistry, molecular immunology, molecular biology, and gene therapy).
Aim I will assess the effectiveness of two clinically-relevant forms of HSC therapy (i.v. HSCs and cytokines) in two different models designed to simulate reperfused and nonreperfused MI and will define the time-window of efficacy. Three clinically-applicable cytokines (G-CSF, SCF, FL) will be tested, alone or in combination. Using gene targeted mice and immunologic blockade of integrins, Aim 2 will systematically investigate the role of four specific adhesion molecules (VCAM-1, ICAM-1, P-selectin, and E-selectin) and three specific integrins (VLA-4, VLA-5, and LFA-1) in HSC migration to the infarcted myocardium.
Aim 3 will decipher the role of SDF-1/CXCR-4 interactions in HSC homing and infarct repair, using adenovirus-mediated gene transfer of SDF-1 and CXCR-4.
Aim 4 will explore the differential regenerative capacity of HSCs and FCs harvested from bone marrow vis-a-vis peripheral blood and the underlying mechanisms.
Aim 5 will determine whether FCs induce allogeneic graft tolerance to HSCs via a Th2 cytokine (IL-4 and IL-10)-dependent mechanism. This proposal will yield novel information regarding the ability of i.v. HSCs and various cytokine regimens to regenerate infarcted myocardium, the molecular mechanisms for HSC homing, the potential role of FCs, and the beneficial effects of FL. The results may eventually lead to the development of novel therapeutic strategies in patients with ischemic heart disease.
|Hong, Kyung U; Guo, Yiru; Li, Qian-Hong et al. (2014) c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 9:e96725|
|Bolli, Roberto; Tang, Xian-Liang; Sanganalmath, Santosh K et al. (2013) Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 128:122-31|
|Madonna, Rosalinda; Bolli, Roberto; Rokosh, Gregg et al. (2013) Targeting phosphatidylinositol 3-kinase-Akt through hepatocyte growth factor for cardioprotection. J Cardiovasc Med (Hagerstown) 14:249-53|
|Madonna, Rosalinda; Bolli, Roberto; Rokosh, Gregg et al. (2013) Long-term engraftment and angiogenic properties of lentivirally transduced adipose tissue-derived stromal cells. Mol Biotechnol 54:13-24|
|Sanganalmath, Santosh K; Bolli, Roberto (2013) Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 113:810-34|
|Hong, Kyung U; Li, Qian-Hong; Guo, Yiru et al. (2013) A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice. Basic Res Cardiol 108:346|
|Guo, Yiru; Flaherty, Michael P; Wu, Wen-Jian et al. (2012) Genetic background, gender, age, body temperature, and arterial blood pH have a major impact on myocardial infarct size in the mouse and need to be carefully measured and/or taken into account: results of a comprehensive analysis of determinants of infarc Basic Res Cardiol 107:288|
|Guo, Yiru; Sanganalmath, Santosh K; Wu, Wenjian et al. (2012) Identification of inducible nitric oxide synthase in peripheral blood cells as a mediator of myocardial ischemia/reperfusion injury. Basic Res Cardiol 107:253|
|Cai, Chuanxi; Teng, Lei; Vu, Duc et al. (2012) The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)/NRF2 signaling pathway and cytokine release. J Biol Chem 287:33720-32|
|Guo, Yiru; Tukaye, Deepali Nivas; Wu, Wen-Jian et al. (2012) The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning. PLoS One 7:e41178|
Showing the most recent 10 out of 77 publications