The role of Thymosin beta4 in adult bone marrow stem cell transplantation for cardiac repair
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
3 out of 10 heart attack survivors will encounter untoward complications from the damaged heart within 1 year. Evidence suggests that delivering bone marrow stem cells (BMSCs) to the injured heart can aid repair, possibly through the release of protective proteins. Recent work has demonstrated that a protein, Thymosin beta4 (Tß4), stimulates cells in the outer region of the adult mouse heart to make new blood vessels. Tß4 is produced by BMSCs at high levels and when artificially made Tß4 was injected into mice after a heart attack, a smaller area of heart damage and better heart function resulted. Therefore, we wish to explore if the beneficial effect of BMSCs delivered to injured hearts is mediated by Tß4. We will isolate BMSCs from adult mice and heart attack patients and assess factors controlling Tß4 release in heart attack conditions. By switching on and off BMSC Tß4 production, the effect of Tß4 on the heart will be examined in experimental models using different cultured heart cells and genetically altered mice. Lastly, to understand the body‘s natural Tß4 response to heart injury, blood Tß4 levels will be measured in patients receiving immediate standard care for heart attack and after BMSC transplantation.
Technical Summary
Bone marrow stem cell (BMSC) transplantation is a promising new treatment strategy for cardiac
diseases, potentially by promoting cardiac repair through paracrine factor(s) secretion. Thymosin
beta4 (Tß4) is highly secreted from some BMSCs and is essential in coronary vasculature development and adult neovascularisation. Furthermore, exogenous Tß4 limits infarct size and
enhances cardiac functional recovery in murine acute myocardial infarction (AMI) model. Our research project will explore the role secreted Tß4 plays in cardiac repair following BMSC transplantation. Firstly, we will determine the factors regulating Tß4 secretion from murine and human BMSCs cultured under ischaemic conditions. Biological effects of secreted Tß4 on different cardiac cell types will be tested in vitro by co-culturing them with BMSC conditioned media with or without Tß4 inhibition. Cardioprotective effect in vivo is examined by injecting BMSCs from wild-type or Tß4 knockout mice and/or the conditioned media in murine AMI model. Potential target cardiac cell types labelled in transgenic mice will be tracked after AMI and wild-type or Tß4 knockout BMSC transplantation. Finally, the intrinsic human humoral T?4 response to coronary occlusion, reperfusion and subsequent BMSC transplantation and the endogenous effect on cardiac repair will be assessed using peripheral blood samples taken at appropriate timepoints from patients entered into the REGENERATE-AMI trial at London Chest Hospital. This ongoing clinical trial investigates the effects of intracoronary delivery of autologous BMSCs immediately following standard AMI care of primary percutaneous coronary intervention. The proposed project could deliver a valuable insight into the mechanism of action of cell transplantation and offer novel therapeutic targets for future development. Equally, identification of Tß4 as a secreted cardioprotective factor may establish this as a new independent therapy.
diseases, potentially by promoting cardiac repair through paracrine factor(s) secretion. Thymosin
beta4 (Tß4) is highly secreted from some BMSCs and is essential in coronary vasculature development and adult neovascularisation. Furthermore, exogenous Tß4 limits infarct size and
enhances cardiac functional recovery in murine acute myocardial infarction (AMI) model. Our research project will explore the role secreted Tß4 plays in cardiac repair following BMSC transplantation. Firstly, we will determine the factors regulating Tß4 secretion from murine and human BMSCs cultured under ischaemic conditions. Biological effects of secreted Tß4 on different cardiac cell types will be tested in vitro by co-culturing them with BMSC conditioned media with or without Tß4 inhibition. Cardioprotective effect in vivo is examined by injecting BMSCs from wild-type or Tß4 knockout mice and/or the conditioned media in murine AMI model. Potential target cardiac cell types labelled in transgenic mice will be tracked after AMI and wild-type or Tß4 knockout BMSC transplantation. Finally, the intrinsic human humoral T?4 response to coronary occlusion, reperfusion and subsequent BMSC transplantation and the endogenous effect on cardiac repair will be assessed using peripheral blood samples taken at appropriate timepoints from patients entered into the REGENERATE-AMI trial at London Chest Hospital. This ongoing clinical trial investigates the effects of intracoronary delivery of autologous BMSCs immediately following standard AMI care of primary percutaneous coronary intervention. The proposed project could deliver a valuable insight into the mechanism of action of cell transplantation and offer novel therapeutic targets for future development. Equally, identification of Tß4 as a secreted cardioprotective factor may establish this as a new independent therapy.