Stem cell research and regenerative medicine have considerable potential to improve human health and quality of life. Karolinska Institutet conducts research at the international frontline in several areas of stem cell biology and regenerative medicine. To strengthen this even more, Karolinska Institutet has established a strategic research area in stem cells and regenerative medicine – StratRegen.
Research in StratRegen spans a broad spectrum of projects, ranging from understanding fundamental aspects of stem cell differentiation to novel strategies for bone marrow transfer and biosynthetic organ generation.
Impact on society
Although there are still a number of problems that need to be overcome before cell therapy becomes a reality for these and other diseases, there is reason to be optimistic, given the progress in the field during the last few years. Since the discovery of ES cells less than three decades ago, the field is now in a state of rapid progress, and during the last three years, we have witnessed the genesis of iPS technology and new ways of reprograming cells into alternative fates, for example in the pancreas. It is of note that these, and other discoveries, not only open new perspectives to obtain cells for transplantation, avoiding immune rejection problems, but can also generate large number of cells from patients with complex genetic diseases for in vitro studies, leading to new insights into the molecular basis of the disorders.
However, the complexity of all these research areas should not be underestimated, and genuine progress at the global level is only likely to take place in a large research organization, such as Karolinska Institutet, which can mobilize expertise in all necessary areas of preclinical and clinical research.
In addition to the direct value in a societal perspective, the projects in this proposal are of strategic importance to the business sector, ranging from big pharma to small biotech companies.
Five research areas
The five research areas addresses fundamental questions, build on leading research at Karolinska Institutet and have the potential to make significant contributions at the highest international level with regard to new scientific concepts, technologies and therapies. The research areas cover the entire spectrum from basic to clinical science and foster cross-disciplinary work, allowing clinical problems to be rationally approached by the latest molecular technology, and, conversely, new concepts from basic research to be rapidly transferred into a clinical setting. The five program areas are:
1. The molecular basis of cellular differentiation
The molecular basis of stem cell differentiation is explored. Mechanisms controlling stem cell maintenance versus differentiation, cell cycle control and cell-intrinsic and cell-extrinsic mechanisms controlling fate decisions will be studied in a number of stem cell types, such as neural stem cells, ES cells, mesenchymal stem cells, cardiac, liver and tooth progenitors. We will also analyze how the differentiated state is normally maintained in vivo to avoid phenotypic drift, and how the differentiated fate can be reprogrammed into alternative fates, both in vitro and in vivo. The molecular basis of reprogramming and induced pluripotency state (iPS) transitions will be studied. The vision is to acquire a deep understanding of molecular principles for state maintenance and fate choices for a broad range of stem cell types.
2. Steering stem cell differentiation to fates of medical interest
Protocols for differentiation of various stem cells into cell types are developed, tailored to areasof unmet medical need, such as Parkinson’s disease, myocardial infarction, muscle disease and orthopedics. Ongoing work on neuronal, cardiac, hepatic, intestinal, bone and dental cell differentiation will be continued and complemented by work in other cell lineages, such as myogenic and hematopoietic lineages. Steering of endogenous stem cell fates in vivo will be pursued, for example to promote oligodendrocyte at the expense of astrocyte differentiation in spinal cord injury models. Finally, novel differentiation protocols will also encompass xeno-free and full GMP (good manufacturing practice) cell culture conditions. The vision is to provide a range of ex vivo-cultured cell types that are candidates for cell therapy for specific diseases, for which transplantable cells currently do not exist.
3. Transplantation biology
Several issues in cell therapy is addressed to further improve survival and bring therapy to new patient groups. ASCT is a life-saving therapy, and Karolinska Institutet carries out nearly 50% of all ASCT in Sweden, but there are still considerable post-ASCT problems, such as leukemic relapse, lethal graft-versus-host disease (GVHD) and opportunistic infections in the wake of immunosuppression. We will develop novel biomarkers for early detection of leukemic relapse, infections, GVHD and hostversus- graft disease (HVGD) and pioneer novel immunoreconstitution strategies. The molecular basis of the immunosuppressive activity of mesenchymal stem cells, which can reverse life-threatening GVHD, will be studied. The vision is to further enhance survival in current transplantation regimens and to develop new transplantation techniques.
4. Decoding cell lineage at the organism level
Currently, cell lineage cannot be traced in more complex organisms, which hampers our understanding of organ and tissue organization and of several important medical problems. Investigators at Karolinska Institutet are in the process of developing novel technology that will make lineage tracing feasible at an unprecedented scale at the organism level, and this technology will be applied to trace lineage in several organs but also in disease situations, including leukemic relapse following ASCT and cancer stem cells in metastatic cancers. The vision is to be able to develop a lineage map for major organs in the body and for cells in specific diseases.
5. Biomaterials for stem cell differentiation and transplantation
Expertise at Karolinska Institutet in biomaterials and nanobiology will be integrated with stem cell research and the clinic to develop new, more in vivo-like culturing conditions for stem cells in vitro and to provide scaffolds to enhance efficacy of stem cell transplantation, for example in orthopedics, cardiology and skin grafting. The vision is to reproduce in vivo conditions in vitro to gain insights into cell differentiation and to improve ex vivo stem cell culture for the development of novel cell therapy strategies.
Center for Hematology and Regenerative Medicine – HERM – is an interdisciplinary translational research environment and educational platform dedicated to hematology, immunology and regenerative medicine. HERM was created during 2011 with a aim to join research groups within hematology and hemopoietic cell therapy at Karolinska Institutet in a new translational research environment.
The vision is to bring together basic and clinical competences to pursue cutting-edge research improving the understanding of cellular and molecular mechanisms involved in normal and dysregulated hematopoiesis and tissue regeneration. The ultimate goal is to translate novel scientific findings into the clinic, thereby improving patient outcome.
The establishment of HERM was supported by a generous grant from the Wallenberg Institute of Regenerative Medicine (WIRM) and by support from the Department of Medicine, Karolinska Institutet, and the Karolinska University Hospital.