Maintenance and Differentiation of Stem Cells
in Development and Disease
Scientific Outline of the Collaborative Research Centre
The basic principles controlling stem cell self-renewal and differentiation are strikingly conserved during evolution, while at the same time regulatory pathways can differ between various stem cell systems in the same organism and between homologous stem cell niches in different organisms. Since the circuits controlling stem cell function in highly complex mammalian systems are often difficult to study and frequently show significant molecular redundancy, our consortium also takes advantage of simpler model systems to illuminate the cellular and molecular mechanisms governing stem cell function.
The long-term goal of the Collaborative Research Center SFB873 is to define the regulatory principles underlying the balance between maintenance, expansion and differentiation of stem cells in diverse systems on a mechanistic level.
This question is tackled by studying intrinsic and extrinsic control of stem cell behavior in various tissues, such as blood, nervous system, or gut in a wide range of model systems including Arabidopsis, Hydra, Drosophila, Medaka, Xenopus, as well as mouse and human. In addition to analyses of normal stem cell function, we focus on diseases such as cancer, since they not only can serve as steppingstones for future translational research, but also represent important models for stem cell dysregulation. During the first funding period of the SFB873 the individual subprojects were firmly established and first important results obtained, collaborations between research groups working on diverse stem cell systems and model organisms were initiated and promising new directions emerged. These range from the use of quantitative approaches, such as biophysical analyses with single cell resolution, to whole genome approaches to describe stem cell regulation at the systems level. It has also become evident that rigorous in vivo lineage tracing experiments are critical to fully understand the flux of cells through highly complex self-renewal and differentiation pathways and these novel developments are well reflected in the proposal for the second funding phase. Since the experimental strategies outlined above will generate substantial amounts of quantitative data, standardized data extraction and mining, as well as mathematical modeling have become essential for an increasing number of projects. Thus, the SFB873 will integrate these aspects into the core research program for the next funding period. Taken together, the challenge and motivation for the second funding phase is to bridge the gap between cell-based and in vivo approaches in experimentally amenable reference organisms and highly complex mammalian systems.
Consequently, the SFB873 is structured into two major focus areas to facilitate interactions:
(A) Mechanisms of stem cell self-renewal
Using suitable model systems of lower complexity we will elucidate essential molecular mechanisms of stem cell control and identify conserved and divergent regulatory modules governing the fundamental decision process of self-renewal and differentiation. These results serve as a resource for comparative studies in more complex systems including mouse and human to define the pathways regulating stem cell fate during development and disease.
(B) Cell-cell interactions in the stem cell niche
In addition to cell-intrinsic mechanisms, extrinsic cues mediated by the microenvironment, commonly referred to as the stem cell niche, maintain stem cell fate and control the balance between self-renewal and differentiation. This group of subprojects focuses on the nature and function of the cell types comprising the niche and on the molecules involved in the bi-directional cross talk between the niche and the corresponding stem cells in normal and disease states. Cross species and cross kingdom comparisons are used to identify the most relevant components that generate the functional stem cell-niche units.
In summary, our initiative centers on two key aspects of stem cell biology, namely control of self-renewal and stem cell-niche interactions, and approaches these features in a number of diverse model systems in vitro and in vivo. Addressing similar questions across species and kingdom boundaries, our consortium will open new avenues in identifying the fundamental components of stem cell control circuitries and relate validated molecular functions of core regulatory modules with abnormal stem cell behavior during the development of human diseases.
Stem cells are the driving force for multicellular development and their controlled activity underlies initiation, growth and homeostasis of tissues and organs in plants and animals. However, this potency does come at a price, since defects in the regulation of stem cell behavior frequently cause lethality irrespective of organism or stem cell type. It follows that evolution has brought about elaborate regulatory systems to ensure appropriate regulation of proliferation and differentiation during diverse developmental stages, environmental and metabolic conditions and across divergent stem cell systems. Furthermore, evolution has driven diversification of stem cell systems and thus underlying regulatory mechanisms to best serve the particular organism in its individual ecological niche. Importantly, several of these systems have become experimentally amenable, opening new avenues to exploit evolutionary diversity for mechanistic research. Research within the SFB873 aims at leveraging this diversity to elucidate the inherent properties of specific models, but also to uncover common and divergent logic, regulatory regimes and molecular signatures of stem cell systems. To this end our consortium brings together internationally recognized researchers, including seven ERC grantees, with unique scientific strengths in cell biology, biophysics, developmental biology, molecular medicine or modeling, working on diverse stem cell systems from single cells to whole organisms, including plants, lower metazoans, insects, vertebrates and human.
Ultimately, we expect to advance our understanding of stem cell regulatory mechanisms during development, homeostasis and disease at the mechanistic level and thus open new avenues for further basic research, as well as translational approaches.
The scientific concept of the SFB873 is centered on the idea of 3-dimensional integration of research topics. In this matrix, the X-axis defines the specific stem cell system under investigation, while the Y-axis refers to the scale of analysis, ranging from molecules to cells to entire organisms and the Z-axis describes the organism in which the studies are being carried out. Viewing projects in this matrix highlights the manifold opportunities for cooperation at the various levels. These include, but are not limited to the exchange of tools for projects using the same organism, collaboration at the mechanistic level in case of projects addressing related molecules, and comparative analyses of design principles and regulatory logic for projects using diverse organisms (see also point 1.2.3.).
The central goals of the SFB873 during the first funding phase were to firmly establish the individual subprojects, initiate meaningful collaborations among more closely related projects, collect a solid data baseline for comparative analyses among more distantly related stem cell systems and to create a lively and interactive stem cell research community on the Heidelberg life-science campus. We have achieved all of these goals (see below) and will now leverage the experimental expertise developed in the diverse subprojects to expand comparative approaches and include more divergent systems. To this end we will use centralized bioinformatic analyses and data mining support provided by subproject Z04 (Boutros/J. Lohmann) and mathematical modeling performed by subproject B08 (Marciniak-Czochra) to guide broader exchange of data and derived logic. We will rigorously test unifying hypotheses obtained by these activities in individual model systems. For the third funding phase, we envision to bring these collaborative initiatives back to the mechanistic level to arrive our long-term goal of defining the regulatory principles underlying the balance between maintenance, expansion and differentiation of stem cells in diverse systems in vivo.