Reports from our institute for the yearbooks of the Max Planck Society

The loss of bone mass is an important aspect of ageing and can cause a disease called osteoporosis. Research results show that blood vessels play a central role in the formation and maintenance of bone mass. While some blood vessels promote the formation of new bone, others regulate the balance between bone-forming and bone-degrading cells. Blood vessels in the skeletal system and their function change fundamentally with increasing age.

Atherosclerosis is a degenerative disease of the vessel wall. In leaky regions of the endothelial cell layer of arteries, lipid particles enter the vessel wall and trigger plaque formation. This happens preferentially in regions where curvature and vessel junctions slow down the blood stream and cause turbulences whereas in long and straight regions, rapid and laminar blood flow protect against leaks. We have found a mechanism that explains how rapid laminar flow protects against endothelial leaks. The molecular basis of this mechanism revealed potential targets for reducing atherosclerosis.

The successful application of synthetic materials for tissue engineering and regeneration depends on the ingrowth of blood vessels from the surrounding host tissue. In order to determine the required materials parameters, we have developed the first cell culture model that mimics the natural process of blood vessel formation in a synthetic tissue environment with independently tunable parameters.

Early stages of mammalian embryos are able to enter a naturally occurring dormant state (diapause) to slow their development during unfavorable environmental conditions. Surprisingly, we found that these seemingly “sleeping” embryos exhibit dynamic cell-cell communication and shape-shifting tissue architecture during stasis, which is required to maintain their long-term developmental potential.

The overexpression of four specific transcription factors allows for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), which can give rise to all cell types of the adult body. We found that overexpression of one of these factors,  Oct4, causes epigenetic changes that deteriorate the quality of the resultant iPSCs. Excluding Oct4 from the reprogramming cocktail leads to iPSCs with unprecedented developmental potential.

The correct three-dimensional organisation of chromatin in the nucleus is a fundamental requirement for the proper functioning of the genome. As such, mutations in elements that determine this architecture lead to developmental disorders and cancer. In this work, chromatin conformation profiling in tightly staged Drosophila embryos revealed a dramatic reorganisation of chromatin that coincides with the zygotic genome activation.

The circulatory system not only supplies the body with oxygen and nutrients, but might also carry toxic compounds and pathogens. To enhance protection of the brain, cerebral blood vessels build the so-called blood-brain barrier. Our studies of the zebrafish brain vasculature show that blood vessel growth and building of the blood-brain barrier are coordinated by two interacting signaling pathways. As the same principles also apply to mammalian cells, the balance of these signaling pathways could be of relevance for human pathological conditions and their treatment.

Pluripotent stem cells represent an amazing tool box for generating virtually any cell tissue of the human body such as, for instance, spontaneously beating cardiac muscle tissue. How this actually works and how the process can be controlled better was recently revealed. Two regulatory switches inside the cells need to be manipulated at the right time. This surprisingly simple procedure may be used for studying the mechanisms underlying genetic cardiac disorders and for evaluating putative drugs.

Proteins are the workhorses of our cells. To fulfill their roles they need to adopt a functional conformation. Scientists have now experimentally determined how fast proteins are made and have shown that the correct speed is critical for functional folding. Perturbing translation leads to protein aggregates. This can cause severe developmental defects in mice. Their brain cells receive the wrong differentiation signal due to protein stress. These results answer a fundamental question of molecular biology and have far reaching consequences for neurodegenerative diseases and biotechnology.

Blood vessels provide the whole organism with essential oxygen and nutrients, but are also an important source of regulatory cues in many organs. In the skeletal system, specialized capillaries release signals that control bone-forming progenitor cells and thereby bone growth. The aging organism lacks such specialized blood vessels and shows a detrimental decline in bone renewal. New results indicate that the stimulation of blood vessel growth in such conditions might be therapeutically beneficial.

Planarians are known as masters of regeneration: they can re-build any part of their body after amputation. This ability relies on a large amount of pluripotent stem cells. To further investigate the mechanisms of how planarians maintain their stem cell pool over generations, scientists have now established a method for analyzing the composition of planarian stem cells and the turnover of their proteins. They discovered a protein that is not only required for the maintenance of the stem cell pool in planarians, but which might also be active in the pluripotent stem cells of mammals.

Our heart pumps blood through an interconnected network of tubules to all parts of our body. This is important for the optimal availability of oxygen to every organ. How does the vasculature ensure the optimal connectivity between blood vessels? Scientists from the Max Planck Institute for Molecular Biomedicine show that differences in blood flow can control the proper sprouting and pruning of blood vessels. These discoveries could provide answers to the question why in certain disease settings, blood is not delivered efficiently.

Leukocyte recruitment into tissue forms the basis of immune surveillance and proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter receptors, followed by rolling and integrin-mediated arrest. Rolling leukocytes collect different inflammatory signals that can activate signaling pathways leading to leukocyte adhesion and transmigration. Several pathways exist that ensure rapid and efficient integrin activation on leukocytes. On the other hand, mechanisms that counteract and balance integrin activation also exist.

Researchers at the MPI for Molecular Biomedicine could define one of two possible routes as the major pathway for leukocytes that leave the blood system and enter into inflamed tissue. In addition, they could identify a switch that allows to open the passage through the blood vessel wall. These results could lead to the development of novel therapeutics to treat inflammation.

Blood and lymph vessels are the conduits of our body. Arteries provide nutrients and oxygen for the tissues, while veins remove metabolic waste and carbon dioxide. Strictly separate from the blood circuitry runs the lymphatic system, which returns interstitial fluid and immune cells into the venous circulation and therefore is essential for immunity. Separation of the vascular systems is an active process in which blood cells play a major role: They can influence the growth of lymphatic vessels. This is of significance for the development of future therapies for vascular diseases.

Researchers of the MPI for Molecular Biomedicine have discovered a novel molecular switch that can promote or block the growth of new blood vessels. This control mechanism involves the balance between two cell surface proteins with opposing functional roles, which decide whether new vascular sprouts and branch points will be formed. These results could open up new avenues for the treatment of vascular disease and cancer.

Researchers of the MPI for Molecular Biomedicine in Münster have made an important advancement towards obtaining patient-specific stem cells. They have succeeded in resetting adult somatic cells to an embryonic original state with less intrusions than previously necessary: instead of a „cocktail“ of four genes, the scientists needed merely two. This could make future stem cell therapies simpler and safer.

Nature hasn’t made things easy for mammals. Admittedly, as any other vertebrate – they develop from a fertilised egg, but unlike fish or frogs, the embryo cannot prosper by itself. Only if it succeeds, after having divided a couple of times, in implanting with its outer cells in the womb, its inner cells will create a foetus. It has long been unclear as to when and how the cells of an embryo pursue various lineages. Scientists of the MPI for Molecular Biomedicine in Münster have now advanced a great deal towards unravelling this mystery.

Endothelial cells form the inner cell layer of blood vessels. They determine when and where within the organism leukocytes enter from the blood into tissue. This step initiates the process of inflammation and keeps it alive. Understanding the molecular basis of cell cell recognition and capturing of leukocytes to the endothelium, as well as the mechanism of leukocyte-transmigration through the blood vessel wall (diapedesis) are the major research goals for the Department of Vascular Cell Biology at the MPI for Molecular Biomedicine in Münster.

Somatic Cells can be reprogrammed to pluripotency by fusion with embryonic stem cells. Factors involved in this process appear to be associated with the nucleus of pluripotent cells and give rise to reprogrammed, pluripotent cells from neuronal precursor as well as terminally differentiated cumulus cells. Their differentiation potential is unrestricted but these cells have a doubled chromosome set, which is addressed in current research projects of the MPI for Molecular Biomedicine in Münster.

In order to fight infections, leukocytes need to access microbes in tissues by extravasating from the flowing blood. This process that initiates inflammation and keeps it alive is controled by endothelial cells that form the interphase between blood and tissue. Whereas the mechanism of capturing leukocytes to the blood vessel wall at sites of inflammation is rather well understood, very little is known about how leukocytes actually overcome the blood vessel wall (diapedesis). It is considered as likely, although still controversially discussed by some, that leukocytes move into tissue by penetrating through the junctions of endothelial cells. One of the major goals of research of the department Vascular Cell Biology at the MPI for Molecular Biomedicine is to identify and understand the molecular mechanisms that allow paracellular diapedesis.

In order to reproduce and to ensure species perpetuation, mammals must produce germ cells, i.e., oocyte and sperm cells. In culture, embryonic stem cells differentiate into oogonia, enter meiosis and produce support cells that have follicle-like structures. They further develop into structures very similar to those found in early stages in mouse embryonic development. The use of oocytes derived in culture is important for biological research and various medical applications. This in vitro system can facilitate biological studies, for example, functional studies for induction of PGCs, interaction between somatic cells and germ cells or studies in genetic reprogramming after nuclear transfer into oocytes. We also see a very large potential in medical applications. We believe that through the derivation of oocytes in culture, fundamental understanding of fertility and problems in infertility can be best researched, and through this in vitro system positive and harmful affects can be ascertained. A major initiative will be to use these artificially derived oocytes for nuclear transfer, to study gene function and genetic reprogramming in a defined system and for production of one’s own embryonic stem cells.