Interuniversity Attraction Poles (IAP) Phase VII (2012-2017)
Project IUAPVII-07: DevRepair
Paracrine and transcriptional control of cell differentiation in organ development and repair
What is DEVREPAIR?
- History of the DEVREPAIR network throughout the different IAP programme phases
DEVREPAIR is a new IAP network that succeeds to previous, positively evaluated and highly collaborative 5-year IAP-V-35 and 5-year VI-20 Belspo projects (coord: J. Martial). IAP-V-35 itself emanated from a strategic decision of J. Martial (at ULG) and D. Huylebroeck (at KUL) to join forces between molecular biologists and representatives of the small developmental biology community in Belgium at that time.
DEVREPAIR, about 10 years later, was primarily the result of an equally strategic decision made by a number of these molecular embryologists of IAP-VI to start merging via IAP-VII their research in signalling (by growth factors, receptors and downstream effector proteins and transcription factors, TFs), i.e. the core activities of IAP-V/VI, with – and this was new, also for Belgium – stem cell researchers and pre-clinical, translational researchers.
Only the Huylebroeck/Zwijsen (KUL) and Peers/Voz (ULG) teams of IAP-V and VI, and Mummery/Chuva (LUMC) of IAP-VI, continued in DEVREPAIR. They are strongly committed to integrate their fundamental research in DEVREPAIR-type of research. At the same time their continuation in DEVREPAIR consolidated the embryology-centric studies (e.g. on BMPs/Nodal in the mouse, diverse studies of stem cell differentiation, and studies of TFs in pancreas formation in zebrafish) and allowed DEVREPAIR to expand the stem cell work force.
- Summary of the general objectives of the DEVREPAIR research project
The strong willingness to implicate the aforementioned leading partner budgets and the agreement to reduce the leading partner number whilst maintaining all teams and hence also share the budget, illustrates two expected key assets of DEVREPAIR, i.e.
- the strong determination to integrate in this forward looking project and partnership the complementary expertise of sufficient teams, thereby creating immediately a strong work force of significant critical mass, and,
- as in IAP-V and VI, support the career building and the research of emerging teams and their leaders.
In brief, the major objective of DEVREPAIR was to strengthen the links between basic research on embryonic development and the repair of selected adult tissues and organs. For this, DEVREPAIR anticipated a 2-step strategic merger of expertise, to be brought together in what can best be described as virtual institute:
Step 1: Merging developmental biology with stem cell basic research: a fundamental goal of biology is to understand the molecular basis of cell identity, and how such identity can be maintained or acquired in vivo and also in vitro. The progressive changes from the totipotent zygote to pluripotent stem cells in the early embryo and subsequently germ-layer and tissue-specific stem/progenitor cells, and ultimately the generation of all mature cells and perfectly shaped tissues and organs, have been studied by embryologists in animal models, including mice (and mutant mice) and different types of stem/progenitor cell derived from the mouse embryo or adult mouse. Progressive loss of potency and acquisition of lineage specification are regulated at the epigenetic, transcriptional and post-transcriptional levels, and are mediated by polypeptide growth factors, chiefly members of the Wnt, TGFβ (in particular Nodal and BMPs), Hedgehog (Hh) and FGF families, and ligands that act via Notch receptor. The respective ligand-receptor interactions influence cell responses via their signal transduction pathways that converge on specific targets, including TFs. Their activity and/or gene expression is then modified, with a growing attention to the chromatin context of these regulated genes and the target genes for the respective, and dynamic, TF complexes, necessitating in DEVREPAIR the inclusion of TF/chromatin experts (e.g. INT2). The growth factors studied in DEVREPAIR thus steer cell fate and determination through combining their extrinsic control with an intrinsic one that emanates from key TFs and their protein complexes in the target cell.
Stem cell researchers study self-renewal, maintenance and gradual loss of potency, which accompanies differentiation of ESCs and tissue-specific stem cells. Of note, recent studies have shown that the reverse process, i.e. gain of potency, by re-programming terminally differentiated cells into pluripotent cells (iPSCs) by transfection or transduction of combinations of key TFs, alone or in combination with chemicals. Thus, human pluripotent stem cells (PSCs) can be isolated from embryos or created from differentiated cells, while tissue-specific stem cells can also be isolated from multiple tissues. If efficient methods for differentiation could be developed, a number of progeny cell types of such stem cells may eventually be suitable for therapy, including in tissue/organ repair. The approach involving transfection of TF-coding sequences has been furthered through the forced synthesis of TFs typical for terminally differentiated cells in somatic cells, causing the alteration in cell fate from e.g. fibroblasts to neurons, cardiomyocyte-like cells and chondrocytes. In addition, if the molecular mechanisms responsible for such differentiation are better understood, it may also be possible to identify key signalling events that are “drugable”, such that improved differentiation of an endogenous pool of tissue-specific stem cells can be used as therapy approach.
Step 2: Merging basic research on developmental signalling further with tissue/organ repair: the establishment of protocols for isolation of hESCs and of tissue-specific stem cells from almost any tissue, and the fact that somatic cells can be re-programmed to acquire pluripotent features, provides unparalleled opportunities in many aspects of medical diagnosis and therapies. Examples are
- the creation of models of human development, which hitherto could only be deduced from studies in mainly the mouse,
- the development of models of human disease via the use of hESCs, creation of iPSC or isolation of tissue-specific stem cells from individuals with a mono/poly-genic disorder,
- the improvement of tools, i.e. the equivalent of mature human cells or tissues, which can be used for the discovery or testing of drugs, and ultimately to generate cells and tissues for transplantation to treat disease.
Although the medical potential of hPSCs is promising, fulfilling it will require that one fully understands the molecular mechanisms that govern pluri- versus multi-potency that enable us to recreate pluripotency from less potent cells and obtain highly specific lineage differentiation. For such goals, stem cell workers have thus far relied on similar aspects that govern embryonic and early post-natal development, studied by embryologists for the last 2-3 decades in zebrafish, Xenopus and mouse. It was our firm belief in DEVREPAIR that only by continuing to apply insights gained from developmental signalling in in vivo embryogenesis in these different species, stem cell biologists will be capable of gaining insights in stem cells themselves and in mechanisms to generate specific cell types from stem cells. The latter cells would then be ideally suitable to use for drug discovery, functional evaluation in preclinical models of human disease, and ultimately clinical applications as well, for which DEVREPAIR also sets the first, careful “translational” steps.
Schematic representation of the different biological systems (processes, cell lineages, animals) brought together and studied by partners in DEVREPAIR for achieving its ambitious goals.