ERC FUNDED PROJECTS

New generations of devices for tissue engineering (TE) should rationalize better the physical and biochemical cues operating in tandem during native regeneration, in particular at the scale/organizational-level of the stem cell niche. The understanding and the deconstruction of these factors (e.g. multiple cell types exchanging both paracrine and direct signals, structural and chemical arrangement of the extra-cellular matrix, mechanical signals…) should be then incorporated into the design of truly biomimetic biomaterials. ATLAS proposes rather unique toolboxes combining smart biomaterials and cells for the ground-breaking advances of engineering fully time-self-regulated complex 2D and 3D devices, able to adjust the cascade of processes leading to faster high-quality new tissue formation with minimum pre-processing of cells. Versatile biomaterials based on marine-origin macromolecules will be used, namely in the supramolecular assembly of instructive multilayers as nanostratified building-blocks for engineer such structures. The backbone of these biopolymers will be equipped with a variety of (bio)chemical elements permitting: post-processing chemistry and micro-patterning, specific/non-specific cell attachment, and cell-controlled degradation. Aiming at being applied in bone TE, ATLAS will integrate cells from different units of tissue physiology, namely bone and hematopoietic basic elements and consider the interactions between the immune and skeletal systems. These ingredients will permit to architect innovative films with high-level dialogue control with cells, but in particular sophisticated quasi-closed 3D capsules able to compartmentalise such components in a “globe-like” organization, providing local and long-range order for in vitro microtissue development and function. Such hybrid devices could be used in more generalised front-edge applications, including as disease models for drug discovery or test new therapies in vitro.

2 498 988 €

Start date: 2015-12-01, End date: 2020-11-30

Genome stability relies on accurate partition of the genome during nuclear division. Proper mitosis, in turn, depends on changes in chromosome organization, such as chromosome condensation and sister chromatid cohesion. Despite the importance of these structural changes, chromatin itself has been long assumed to play a rather passive role during mitosis and chromosomes are usually compared to a “corpse at a funeral: they provide the reason for the proceedings but do not take an active part in them.” (Mazia, 1961). Recent evidence, however, suggests that chromosomes play a more active role in the process of their own segregation. The present proposal tests the “active chromosome” hypothesis by investigating how chromosome morphology influences the fidelity of mitosis. I will use innovative methods for acute protein inactivation, developed during my postdoctoral studies, to evaluate the role of two key protein complexes involved in mitotic chromosome architecture - Condensins and Cohesins. Using a multidisciplinary approach, combining acute protein inactivation, 3D-live cell imaging and quantitative methods, I propose to investigate the role of mitotic chromosomes in the fidelity of mitosis at three different levels. The first one will use novel approaches to uncover the process of mitotic chromosome assembly, which is still largely unknown. The second will explore how mitotic chromosomes take an active part in mitosis by examining how chromosome condensation and cohesion influence chromosome movement and the signalling of the surveillance mechanisms that control nuclear division. Lastly we will evaluate how mitotic errors arising from abnormal chromosome structure impact on development. We aim to evaluate, at the cellular and organism level, how the cell perceives such errors and how (indeed if) they tolerate mitotic abnormalities. By conceptually challenging the passive chromosome view this project has the potential to redefine the role of chromatin during mitosis.

1 492 000 €

Start date: 2015-10-01, End date: 2020-09-30

The interplay between intestinal microbes and immune cells ensures vital functions of the organism. However, inadequate host-microbe relationships lead to inflammatory diseases that are major public health concerns. Innate lymphoid cells (ILC) are an emergent family of effectors abundantly present at mucosal sites. Group 3 ILC (ILC3) produce pro-inflammatory cytokines and regulate mucosal homeostasis, anti-microbial defence and adaptive immune responses. ILC development and function have been widely perceived to be programmed. However, recent evidence indicates that ILC are also controlled by dietary signals. Nevertheless, how ILC3 perceive, integrate and respond to environmental cues remains utterly unexplored. We hypothesise that ILC3 sense their environment and exert their function as part of a novel epithelial-glial-ILC unit orchestrated by neurotrophic factors. Thus, we propose to employ genetic, cellular and molecular approaches to decipher how this unconventional multi-cellular unit is controlled and how glial-derived factors set ILC3 function and intestinal homeostasis. In order to achieve this, we will assess ILC3-autonomous functions of neurotrophic factor receptors. ILC3-specific loss and gain of function mutant mice for neuroregulatory receptors will be used to define the role of these molecules in ILC3 function, mucosal homeostasis, gut defence and microbial ecology. Sequentially we propose to decipher the anatomical and functional basis for the enteric epithelial-glial-ILC unit. To this end we will employ high-resolution imaging, genome-wide expression analysis and tissue-specific mutants for define target genes. Our ground-breaking research will establish a novel sensing program by which ILC3 integrate environmental cues and will define a key multi-cellular unit at the core of intestinal homeostasis and defence. Finally, our work will reveal new pathways that may be targeted in inflammatory diseases that are major Public Health concerns.

2 270 000 €

Start date: 2015-07-01, End date: 2020-06-30

Fighting microbial infection of wounds, especially in immunocompromised patients, is a major challenge in the 21st century. The skin barrier is the primary defence against microbial (opportunistic) pathogens. When this barrier is breached even non-pathogenic fungi may cause devastating infections, most of which provoked by crossover fungi able to infect both plant and humans. Hence, diabetic patients (ca. 6.4% of the world population), who are prone to develop chronic non-healing wounds, constitute a major risk group. My research is driven by the vision of mimicking the functionality of plant polyesters to develop wound dressing biomaterials that combine antimicrobial and skin regeneration properties. Land plants have evolved through more than 400 million years, developing defence polyester barriers that limit pathogen adhesion and invasion. Biopolyesters are ubiquitous in plants and are the third most abundant plant polymer. The unique chemical composition of the plant polyester and its macromolecular assembly determines its physiological roles. This lipid-based polymer shows important similarities to the epidermal skin layer; hence it is an excellent candidate for a wound-dressing material. While evidences of their skin regeneration properties exist in cosmetics formulations and in traditional medicine, extracting polyesters from plants results in the loss of both native structure and inherent barrier properties hampering progress in this area. We have developed a biocompatible extraction method that preserves the plant polyester film forming abilities and their inherent biological properties. The ex-situ reconstituted polyester films display the native barrier properties, including potentially broad antimicrobial and anti-biofouling effect. This, combined with our established record in fungal biochemistry/genetics, places us in a unique position to push the development of plant polyester materials to be applied in wounds, in particular diabetic chronic wounds.

1 795 968 €

Start date: 2015-09-01, End date: 2020-08-31