Stem Cell Research at the Heinrich-Heine-University Düsseldorf
Institute for Transplantation Diagnostics and Cell Therapeutics (ITZ)
The main remit of the Institute for Transplantation Diagnostics and Cell Therapeutics (ITZ) is to centrally produce, develop and characterise stem cell transplants from peripheral blood, bone marrow and cord blood. It has the following facilities at its disposal - the allogeneic Jose Carreras Cord Blood Stem Cell Bank (almost 26,000 cryopreserved transplants), the interdisciplinary GMP unit, the bone marrow donor register (>200,000 allogeneic volunteer bone marrow donors), immunogenetic diagnostics and the Natural Immunity group. New treatment approaches can be swiftly implemented for these stem cell specimens due to manufacturing licences, drug licencing in accordance with the Medicinal Products Act (AMG), and accreditation/certification by international organisations such as FACT/NETCORD, NMDP and ASHI.
Research work and clinical development is currently focussing on characterising haematopoietic transplants, developing immune therapeutics (dendritic cells against tumours) and stromal subcellular populations from cord blood and bone marrow, as well as transplant immunology and tumour stem cells. Our experience in manufacturing clinical products according to GMP guidelines is also used by other departments at Düsseldorf University Hospital (UKD). At the same time, products and cell populations are also placed at the disposal of other local clinics for research purposes.
The automatization of HLA testing (sequencing) by the immunogenetic laboratory is one of the prerequisites for the rapid availability of transplants worldwide and for associated research projects. Cooperation with a wide variety of disciplines within the faculty, for example, surgery and gynaecology, such as within the cancer ID consortium and other cooperation projects with neurosurgery and neurobiology occur on the basis of technical expertise based in the ITZ. One research project with Italy funded by the DAAD is the basis of the molecular genetics and functional signature of osteoprogenitor and cartilage progenitor cells of stromal cells from cord blood, bone marrow and tissue.
In cooperation with the Department of Neurosurgery, the ITZ also manufactures dendritic cell vaccines as part of a clinical multicentre study funded by the Federal Ministry of Education and Research (BMBF). ITZ groups (headed by G. Kögler and M. Uhrberg) are collaborating with the Düsseldorf-based Institute for Stem Cell Research and Regenerative Medicine (ISRM) on the generation and differentiation of human IPS cells.
Institute for stem cell research and regenerative medicine
The newly founded institute for stem cell research and regenerative medicine (ISRM) is embedded with the medical faculty of the university clinic Duesseldorf.
Our research is divided into five inter-related areas
1. Transcriptional and signal transduction mechanisms regulating self-renewal and pluripotency in human embryonic stem cells, carcinoma cells and iPS cells (induced pluripotent stem cells).
We derive (employing viral, episomal plasmids, ES-specific miRNAs and small molecules) and characterise iPS cells from distinct cell types (dermal fibroblasts, keratinocytes, amniotic fluid, chorionic villi, and bonemarrow-derived mesenchymal stem cells), ages and disease states. The main themes of investigation include,
(i) Do iPS cells derived from distinct cell types retain cell type specific gene signatures?, the notion of retention of an epigenetic memory.
What are the long-term effect of these cell type specific gene signatures on self-renewal and pluripotency?.
(ii) Modulating cellular homeostasis via the hypoxia related pathways as a means of ehancing the efficiency of deriving iPS cells
(iii) Identification and functional characterisations of miRNAs that might have roles in the induction and maintenance of pluripotency.
These studies are intended to increase our meagre understanding of the molecular mechanisms underlying cellular reprogramming.
2. iPSC-based derivation of disease models to aid in understanding their etiology
iPS cells derived from individuals afflicted by diseases such as Alzheimer’s, Type II Diabetes, Nijmegen Breakage Syndrome (NBS) and Steatosis provide in vitro models for studying the molecular mechanisms underlying the ontology of these diseases. These studies are carried out in collaboration with experts in systems biology and clinicians.
This project (EU/FP7-HEALTH-2012.2.2.2-1) combines integrative systems biology & comparative genomics for studying human ageing and Alzheimer’s diseases.
livSYSiPS - The systems biology of network stress based on data generated from in vitro differentiated hepatocytes derived from Steatotic-specific human iPS cells.
Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from manageable stress as in simple steatosis (S) to excessive stress as in steatohepatitis (SH). In contrast to simple steatosis which has a good prognosis and may be considered a stressed state of normal liver, SH may ultimately lead to liver cirrhosis and hepatocellular carcinoma, which are both diseased states. A major unsolved problem is the marked difference in the individuals’ ability to deal with the stress, e.g. as observed in terms of risk to develop steatohepatitis and to progress to cirrhosis. These differences in susceptibility to SH and its progression to cirrhosis have been attributed to a complex interplay of genetic and environmental factors. The concept underpinning this project is that the various environmental exposures and genetic factors affect many different molecules in many different ways, but have very similar effects on network function. Hence, shifting focus from individual genes to the networks in which they are embedded, might well lead to a much clearer understanding of molecular mechanisms.The knowledge gained from these studies will be invaluable for the early means of identifying drugs that cause side effects in patients and most importantly for understanding the molecular (genes and associated signalling pathways) mechanisms underlying the etiology of simple steatosis and steatohepatitis.
3. Comparative characterisation of functional hepatocytes and neuronal cells derived from human ES cells and patient-specific iPS cells with the aim of establishing a platform for toxicology studies and drug screens.
4. Systems biology of stem cell fate and cellular reprogramming.
Our aims are two-fold
(i). Network and pathway reconstruction
Identify the gene networks involved in maintaining self-renewal of ES and iPS cells and also cell lineage specification.
(ii). Systems modeling
The maintenance of pluripotency and self-renewal of human ES and iPS cells are intrinsically complex processes driven by the co-ordinated dynamic expression of a plethora of genes, their encoded proteins and associated signalling pathways in response to external signalling cues such as FGF2. Our systems biology approach combines high throughput approaches (ChIP-chip, ChIP-seq, RNAi, metabolomics and cytokine stimulations of hESCs) and advanced computational techniques to dissect the molecular mechanisms of stem cell fate and cellular reprogramming. Finally we have created a user-friendly database (http://biit.cs.ut.ee/escd/index.cgi?gene=oct4&p=0.05&entries)
In silico modeling of gene expression datasets resulting from perturbation experiments pertaining to human ESC and iPSC self-renewal. The ultimate aim is to permit defining crucial components within the reconstructed networks that supporting self-renewal and pluripotency.
5. The effect of age and genome instability on cellular reprogramming and cell type specific differentiation.
We employ iPSC-based models to study age-associated diseases, related gene expression patterns and signal transduction mechanisms using human bone marrow-derived MSCs and dermal fibroblast cells from young and aged individuals as model systems.
Our research on aging is based firmly on the concept that the same signalling mechanisms that regulate the plasticity of stem cells are altered during aging and in age-related diseases. Organ and tissue dysfunction which is readily observable during aging results from a loss of cellular homeostasis and reduced stem cell self-renewal. Since molecular alterations in adult stem cells contribute to regenerative dysfunction, aging and carcinogenesis, we employ cellular reprogramming to investigate the following,
(i). Can somatic cells derived from aged individuals (50–90 yrs) be reprogrammed to pluripotency with the same efficiency as cells obtained from younger subjects? (3 months - 17 yrs)
(ii). Do common features of aging still persist in iPS cells derived from aged individuals?
(iii). Can reprogramming of aged cells be improved by adding drugs that interfere with common pathways associated with the aging process such as the insulin/IGF and mTOR signaling pathways
(iv). Are aged cells more prone to genome instability and chromosomal aberrations upon the induction of pluripotency.
Stem cell research in Düsseldorf plays an important role in national research with its stem cell bank for umbilical cord blood, founded in 1992 (with 293 unrelated transplants given and 9500 cryoconserved umbilical cord blood preparations, currently the largest European stem cell bank, as of December 2005) and the clinical focus of its Interdisciplinary Programmes for Blood Stem Cell Transplantation at the Faculty of Medical Science.
In 1999, the Department for Transplantation Diagnosis and Cell Therapeutics initiated research work focussing on unrestricted somatic stem cells from umbilical cord blood. Researchers were able to develop a robust culture method for the systematic expansion of these adherently growing cells without a spontaneous differentiation occurring.
In order to scientifically, preclinically and finally with regard to their clinical application, define the potential of these somatic stem cells, which are able to functionally differentiate in tissue culture and in preclinical animal models (mouse, rat, sheep) in all three germlines, an interdisciplinary working group was formed at the Medical Sciences Faculty at Heinrich-Heine University in 2001. A number of scientists from the Faculty of Mathematics and Natural Sciences were involved in this joint research group. The group investigated the regulatory and functional mechanisms of pluripotency along with the specific differentiation of these, described here for the first time as stem cells, from cord blood in tissue from bone, teeth, cartilage, fat, nerves, liver, blood, blood vessels and the heart.
Particular attention is devoted to the understanding of the symmetrical and assymetrical cell division programs. The goal is the elucidation of the molecular genetic regulation of self renewal, the development in progenitor cells of various differentiated tissue specificities as well as the extensive proliferation potentiation. This work is now being carried out successfully in the DFG Research group ‘Unrestricted Somatic Stem Cells from Umbilical Cord Blood (USSC)’.A number of reports, open to question, have appeared in scientific literature which want to infer that somatic pluripotent cells from bone marrow come into existence through so-called ‘transdifferentiation’Experiments are, therefore, crucial for stem cell research as a whole, which can prove indisputably the existence of a pluripotent somatic stem cells in the human system. At the current moment in time, there is no clinical evidence of such a cell in fully-grown humans. This brings out the central relevance of our research approach with stem cells from umbilical cord blood.
All clinical stem cell studies, including those already successfully started by clinics for general and visceral surgery, as well as gastroenterology and haepatology for autologous liver generation, are critically reviewed and accompanied by an ethics working group along with the corresponding commission of the Medical Sciences Faculty.The processing of cellular medicinal products from umbilical cord blood (with marketing authorisation from the Paul-Ehrlich-Institute [PEI]) as well as these cell therapeutics and all preparations for bone marrow transplantations and for peripheral stem cells for haematology, pediatrics, gynaecology, urology, endocrinology and neurosurgery has taken place since mid 2005 in the new GMP clean room building of the Institute for Transplantation Diagnostics and Cell Therapeutics.
Clinic for Heart and Thorax Surgery
Furthermore, associates from the Clinic for Heart and Thorax Surgery have managed to begin the first national study, with approval from PEI, on the treatment of heart patients needing an operation through selective precursor cells from bone marrow.Parallel to this, research is currently being carried out in preclinical studies on swine models to see whether the umbilical cord blood stem cells (USSC) specially identified in Düsseldorf can be inserted allogenically in an analogue way. Correspondingly, the immunomodulatory characteristics of these stem cells along with their homing and migration behaviour are being examined in particular. Through their ability to produce a variety of pharmaceutically effective substances with regenerative impact at the cell level in degenerating tissue, such stem cells can develop a regenerative effect even without their own differentiation in tissue specific cells. Targeted research should clarify whether the migration of stem cells into the tumour tissue can be used therapeutically. The possible biological interaction between tumour cells and stem cells with respect to a tumour genesis and progression needs to be illuminated further. Ultimately, it is necessary to elucidate the biological interfaces between stem cells, tumour stem cells and tumour cells, leading to new types of treatment.Gene analyses which focussed on such stem and aligned progenitor cells from umbilical cord blood and bone marrow and tumour stem cells on epigenetic programs and microRNA-controlled regulation mechanisms, have shown the first important results in the definition of a molecular identity of such cells, above all, however, the particular commonalities with embryonic stem cells along with various precursor cells.
These Düsseldorf stem cell research activities are carried out in cooperation with the Medical & Biological Research Centre and the SFB 590 (Inherent and Adaptive Differentiation Processes) as well as within the framework of the Stem Cell Network NRW with the Max-Planck-Institute of Molecular Biomedicine in Münster and the Institute for Regenerative Neurobiology at the University of Bonn. In addition, cooperation with the biomaterial Centre (Biomat) at the Technical University in Aachen should be intensified regarding the use of new types of biomaterials and nanotechnologies.
Your contact at the University Düsseldorf is Prof. J. Adjaye.
You can reach him at 0049 (0) 211 81-08191
Philosophy Institute at the University of Düsseldorf
The Philosophy Institute at Heinrich Heine University in Düsseldorf has a strong teaching and research focus on applied ethics and with its Masters course in philosophy offers the chance to get a Masters degree with applied ethics as a major (in collaboration with the co-operating department of the History of Medicine). The focus is on bio-ethical topics (biomedical ethics, natural ethics) media ethics, business ethics and the ethics of technology. Research projects which have been, and are being, conducted in this field include projects on the topics of "Principles and Application of Future Ethics", "Methodological Issues in Medical and Applied Ethics", "Critical Analysis of Arguments against Selection at the Beginning of Life" and "The Naturalisation of Human Dignity", and “The Limits of Negotiation. On the possibilities and limitations of moral compromise in relationships within intercultural cooperation.”
Your contact person for the philosophical faculty at the University of Düsseldorf is Prof. Dr. D. Birnbacher.
You can reach him at 0049 (0) 211-5590159.
Institute for the History of Medicine
Within the large spectrum of topics constituting the history, theory and ethics of medicine, the Institute for the History of Medicine at Heinrich Heine University Düsseldorf focuses mainly on the interdependence of medicine and society. Methodologically, its approach is based on historical sociology and the theory-driven history of medicine. The following topics are covered: health, disease and body awareness through to molecular medicine; society and health with reference to medical ethics; factors in the development of public health and health policy (includes: medical science and National Socialism), historical demography and epidemiology, the history of the hospital, the scientific history of naturopathy, medical aspects of environmental history, doctors and medical science in Düsseldorf and finally mankind and death in the visual arts (the University’s dance of death collection).