AREA B.1 – Managers
Prof. Dr. Johann Bauersachs
Department of Cardiology and Angiology
Hannover Medical School
PD Dr. Ina Gruh
LEBAO, Department of Cardiac, Thoracic, Transplantation and Vascular Surgery (HTTG)
Hannover Medical School
Prof. Dr. Axel Schambach, PhD
Institute of Experimental Hematology (IEH)
Hannover Medical School
Prof. Dr. Reinhold Förster
Institute for Immunology
Hannover Medical School
Area B.1: Regeneration in Disease Models
Regeneration in Disease Models – this is the common goal of 25 REBIRTH units in Area B1. They are organized into four collaborative research units (CRU) corresponding to the organ systems targeted in REBIRTH, namely the liver, the lung (including vessels), the heart, and the blood system (including research focusing on immunity).
All units follow a translational and interdisciplinary approach to developing new regenerative therapies. Based on cell culture models, we are investigating potential therapeutic approaches while moving forward from rodent and large-animal models to first-in-man trials. Our novel treatment strategies are based, inter alia, on small molecules, RNAi, recombinant proteins or vectors enabling reversible, inducible and dose-controlled interventions. Novel findings in stem cell biology and strong interaction with researchers from Area A facilitate new strategies for cellular therapies including iPSCs or ESCs. Advanced tissue engineering approaches will be used to reconstitute organ integrity in conjunction with novel strategies to induce immune tolerance against transplanted cells and tissue-engineered constructs. It is the aim of Area B1 to advance therapeutic concepts based on endogenous regeneration, gene and cell therapy, tissue engineering, or biohybrid devices, and to carefully choose and adjust these strategies according to the requirements for regeneration in the relevant organ system:
CRU 3: Liver Regeneration
In CRU 3 we aim to explore novel therapeutic strategies for liver regeneration and inherited metabolic liver diseases. Our research involves different animal models; our sights are, however, very much on clinical translation. For example, liver regeneration is investigated in humanized mice. These transgenic animals accept human hepatocyte transplants and can be used to study the molecular mechanism of cell cycle proliferation of human cells. Our research also focuses on the role of the immune system and miRNAs for liver regeneration, and includes hepatobiliary regeneration. Different cell sources are analysed regarding their potential for gene and cell therapies as well as for drug-testing purposes, including pluripotent stem cells, human adult liver stem cells and cells generated by transprogramming of hepatic phenotypes.
CRU 4: Lung and Vessel Regeneration
For lung regeneration and repair in CRU 4, we focus both on device development and on cell therapy strategies. The concept of biofunctionalization is applied in the development of an endothelialized extracorporeal membrane oxygenator (ECMO). This strategy should prolong the (hitherto limited) time the device is functional for gas exchange before its hollow-fibre surface is blocked by adhesion of blood components. In the long run, this could lead to the development of an implantable bio-artificial lung. Further research aims at ex vivo lung regeneration using the Organ Care System (OCS) and at ex vivo gene therapy for cystic fibrosis, with functional repair using cell therapy. CRU 4 also develops new strategies for vascular regeneration; here we investigate, for example, the relationship between senescence, endothelial dysfunction and cardiovascular disease. Cell engineering could allow the generation of tunable ‘synthetic’ cells such as conditionally immortalized human endothelial cells, which form perfused vessels after transplantation into mice.
CRU 5: Myocardial Remodeling and Regeneration
CRU 5 combines units with different strategies for regeneration of the heart. Novel secreted factors can be identified using bio-informatic secretome analyses and will be implemented for non-cell-based strategies toward cardiac regeneration. Our research into the regenerative potential of the cardiac microenvironment will give new insight into the mechanisms of endogenous regeneration, the role of paracrine factors and microRNAs in different cardiac cell types, and the importance of cellular cross-talk. In addition to gene therapy approaches to promoting cardiac function for the treatment of heart failure and pathological hypertrophy, vascular remodelling and regeneration will also be targeted using antagomirs, LNAs, or small molecules, as well as specialized myeloid cell populations for arterial regeneration. Our tissue engineering strategies for the heart aim to provide heart valve prostheses and bio-artificial cardiac tissue for reconstructive therapy, which are tested in small- and large-animal models of cardiovascular disease. For clinical application, we plan to establish non-immunogenic or fully autologous grafts.
CRU 6 'Blood and Immune Regeneration
For regenerative therapies of the blood and immune system, CRU 6 has a strong focus on cell and gene therapy. Novel strategies include enhanced and synthetic cells with improved engraftment and reconstitution potential. We investigate several ‘key players’ in the haematopoietic system, such as haematopoietic stem cells, but also dendritic cells and myeloid cell lineages including granulocytes and monocytes/macrophages. The identification of mechanisms of myelopoiesis and crucial factors for lymphatic regeneration should lead to novel therapeutic concepts based on gene therapy, microRNAs or cellular vaccines. At the same time, we are developing safer systems for gene therapy and new strategies for improved graft survival based on HLA-silenced cells and tissue for transplantation. Our research in CRU 6 focuses both on preclinical validation in animal models, including humanized mice, and on clinical translation.
Projects in Area B1 strongly rely on the regenerative technologies that are developed in Area B2. Our tissue engineering efforts are supported by the development of new regenerative materials; laser engineering facilitates cell and tissue modification; and many regenerative processes could not be analysed in detail without the help of our imaging platform. In the future, we expect even closer interaction with Area C as well, to further advance the ongoing validation and clinical translation of the presented strategies.
By now, research in Area B1 has demonstrated the therapeutic benefit of a number of new strategies in proof-of-concept-studies targeting, for example, various forms of leukaemia. New treatment options have been developed in close collaboration with strong national and international partners. These have been the basis for ongoing clinical trials such as ‘ESPOIR’, a European Clinical Study for the Application of Regenerative Heart Valves, and ‘CATCH-AMI’, which is investigating CXCR4 AnTagonism for Cell Mobilization and Healing in Acute Myocardial Infarction. In addition, researchers have filed a number of patents, among them patents for several miRNA-based therapies to improve cardiac remodelling in mouse models of cardiac disease.