The use of Scaffold-free cell sheet technique to refine mesenchymal stromal cell-based therapy for heart failure

• Grant number: 14/07000-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): September 01, 2014
• Effective date (End): August 31, 2015
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Eduardo Colombari
• Grantee: Prashant Jay Ruchaya
• Supervisor: Ken Suzuki
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Research place: Queen Mary University of London, England

Abstract

Heart failure remains a leading cause of death and disability, requiring early development of new therapies. In addition to peripheral manifestations, central dysfunction leads to an exaggerated sympathetic tone emanating from central cardiovascular regulating nuclei. Research has shown that transplantation of bone marrow-derived mesenchymal stromal cells (MSCs) is a promising new approach. Although cardiomyogenic differentiation of MSCs is not substantial in vivo, MSCs can instead secrete a group of cytokines/growth factors that repair and regenerate damaged myocardium. However, one of the most important issues associated with this approach is that any current cell-delivery method results in very poor donor cell survival, largely limiting the therapeutic efficacy. Therefore, development of a new, more effective method for delivering MSCs into the heart is important for the future success of this approach. Suzuki's group recently developed a novel approach for MSC-delivery to the heart using an innovative bioengineering technology, the cell-sheet technique. Scaffold-free cell-sheets can be generated with unique culture dishes, the surface of which is coated with a temperature-responsive polymer (poly-N-isopropylacrylamide; PIPAAm), without using any artificial scaffolds and without cell-dissociation processes that can damage donor MSCs. We have reported that the epicardial placement of autologous MSC-sheets significantly improved donor MSC engraftment and therapeutic benefits, compared to the current method. This method is now under development towards clinical application. In addition, recent studies have indicated that MSCs have a low immunogenic phenotype and a unique ability to suppress immunological responses by influencing T-cells and dendritic cells. These properties may mean that donor allogeneic MSCs do not provoke immunological rejection after engraftment, proposing the utility of allogeneic MSCs as a donor for cell therapy. This will circumvent the issues associated with the use of autologous MSCs, including reduced viability and functionality of MSCs from aged patients and a protracted time to expand patients' own MSCs. In clinical settings, allogeneic MSC-sheets can be produced with HLA-matched relatives, but our ultimate goal is to develop a "bank" of MSC-sheets from young, healthy volunteers. This system will provide an immediate supply of well HLA-matched and quality-controlled allogeneic MSC-sheets whenever requested. On this basis, clinical trials using allogeneic MSCs for heart failure have actually started, but all these utilize the injection of allogeneic MSC suspensions. We propose to further improve the therapeutic effect of allogeneic MSC-based therapy by using the cell-sheet technique. Suzuki's team is thus running is a large programme to comprehensively validate the efficacy and safety of allogeneic MSC-sheet therapy for heart failure with an aim of clinical application in the near future. This innovative treatment has great potential to achieve the maximal therapeutic benefit from MSC-based therapies in treating the peripheral manifestations associated with heart failure whilst enlarging its indication, representing a major advance in stem cell therapy. However, immunological response in vivo after transplantation of allogeneic MSCs to the heart remains uncertain. The project therefore aims to elucidate the degree, nature, time course, and underlying factors of immunological response of allogeneic MSC-sheets in a clinically relevant in vivo model. In addition we will investigate the beneficial effects of the allogeneic MSC-sheet therapy in central nuclei (the paraventricular nucleus and nucleus of the solitary tract) modulating sympathetic nerve activity which is yet to be determined. (AU)