Within an organism and more particularly at the organs and tissues level, cell behavior is dictated both by cellular interactions with the local environment and by various signals that cells receive from other distant cells or organs, in the form of soluble factors for example. Typically, these interactions and the signals generated in the cell have been characterized as interactions of a chemical nature (phosphorylation, ligand-receptor binding… etc). Although this is true, especially in the context of intracellular signaling, interactions between cells and their environment cannot be restricted only to chemical interactions as physical interactions are also crucial. To evaluate these interactions, cells have developed mechanisms allowing them to evaluate the physical properties of their environment and generate an adequate intracellular signaling, namely mechanotransduction.

As an organ sensitive to mechanical stress, the skin is of particular interest when it comes to mechanotransduction. Specifically, aging induces changes in the extracellular matrix (quality and stiffness) that greatly influence mechanosensitive responses. In the lab, we study the molecular mechanisms of mechanotransduction that allow cells to assess the stiffness of their environment, more particularly in vivo using a skin premature aging mouse model. The viscoelastic properties are determined using atomic force microscopy (AFM). The mechanisms involve integrins, which are adhesion receptors as well as proteins of the adhesion complex. We have also developed in the laboratory a range of molecular and cellular tools that combined with biophysical techniques allow us to generate forces on cells and dissect the intracellular signaling generated. This presentation combines the research data and technical tools used and made available to the scientific community.

The spatial and temporal organization of the cell nucleus and its components is essential for genome regulation. The nuclear envelope (NE) maintains the shape and the mechanical integrity of the nucleus, but also provides an anchor for chromatin that is connected to its inner side. This interaction mediates the regulation of gene expression, DNA replication and the maintenance of genome stability.

In metazoans, the NE is lined by a thin meshwork composed of the nuclear lamina, a family of proteins consisting of A- and B-type lamins. In addition to their structural function, lamins also play a major role in genome organization and stability. This idea is supported by the phenotype of cells from Hutchinson-Gilford progeria syndrome (HGPS), a rare human disease caused by the expression of a mutant form of LaminA called Progerin. These cells display aberrant NE structure, but also genome instability, short and dysfunctional telomeres, and premature senescence entry. Here, I will present the functional link we recently unraveled between NE structure, genome stability and aging, with an emphasis on telomere maintenance.

The loss of elasticity is a hallmark of systemic aging and is amplified in skin photoaging or in genetic syndromes (e.g. cutis laxa) with consequences on tissue functions and social interactions. Soft tissue elasticity is mainly provided by large elastic fibers composed of supramolecular complexes of elastin and microfibrils. In the skin, the mature elastic fibers are located in the dermal compartment, they are tangential to the surface in the reticular dermis to allow the stretching and recoiling of the skin. Fine elastic fibers, poor in elastin, are observed perpendicular to the surface in the papillary dermis and participate in the structuring of the epidermal ridges and the dermal papillae. The synthesis of elastic fibers (elastogenesis) occurs during the last third of fetal life with a peak in the perinatal period and then slowly decreases until the end of growth. In adulthood, elastogenesis is very weak or leads to disorganized and non-functional fibers, while the initial fibers gradually degrade according to a rate depending on lifestyle.

The lack of functional elastic fibers has an impact on cell behavior and morphology. Dermal fibroblasts from aged individuals, or senescent fibroblasts, show specific changes in their nuclear morphology associated to a decrease of circularity and a reorganization of lamins A/C and B. The same modulations can be observed when culturing healthy cells on too soft substrates, demonstrating that the cells adapt their mechanical properties to the elastic modulus of their environment across a physical continuum from extracellular matrix to chromatin. In keratinocytes, a stiff environment promotes cell proliferation, while a soft substrate induces cell differentiation below a specific threshold.

To date, no treatment exits to restore or repair deficient or degraded elastic fibers. A few pharmacological compounds have been proposed, but their efficacy/side effects balance remains very unfavorable. We developed a synthetic elastin protein (SEP) inspired from the human tropoelastin sequence to provide an elastic molecular prosthesis as a substitution material to replace or strengthen endogenous elastic fibers.

The SEP is easily produced in E. coli and purified by inversed transition cycling. The resulting 55 kDa protein recapitulates the main physicochemical properties of the tropoelastin as thermal responsiveness, secondary structures, and spherical self-assembly. The SEP, or its fragments obtained by enzymatic digestion, do not induce pro-inflammatory cytokines (IL-8, -1β and TNFα) from a monocyte cell line, nor neutrophil recruitment after injection in a relevant in vivozebrafish model. Considering post-confluent dermal fibroblasts treated or not with the SEP, the SEP colocalized with fibrillar deposits of elastin, while no colocalization is observed in the presence of an inhibitor of lysyl oxidases (crosslinking enzyme). This indicates that the SEP is actively integrated into pre-existing elastic material by the cellular machinery. Reconstructed dermal sheets treated with the SEP show larger amount of fibrillar structures positive for elastin and SEP compared to untreated samples. Moreover, treated sheets show a 4-fold increase of the elastic modulus (E’). Altogether, these results designate the SEP as a good candidate for improving tissue elasticity.

Keratin proteins form filament networks in skin epidermis and other epithelial sheet tissues. The discoveries that mutations in keratins are the underlying cause of many genetic skin blistering and fragility disorders, notably in epidermolysis bullosa simplex (EBS), highlighted the role of keratins in mechano-stability of the epidermis. Yet although we can see clear morphological defects in the EBS cells (keratin protein aggregates, instead of clean filament networks), the EBS-mutant keratins can still form cytoplasmic filament networks. Thus it is unclear how and why EBS keratinocytes become so fragile. We analysed skin keratinocytes engineered to express fluorescent keratins with and without EBS mutations and found that EBS-mimetic cells show constitutive cell stress with many features of a “keratinocyte activation” wound healing response. Keratinocyte activation processes show overlaps with inflammatory responses and might also render the tissue fragile under mechanical stress. We therefore used these disease stress reporter cells to identify compounds that could reduce stress, hypothesising that reversing cell stress might increase tissue resilience (and thus reduce blistering in EBS skin). Keratinocyte activation upon stress of various kinds is likely to be a fundamental evolutionary function of keratinocytes, to enable rapid closure of potentially life-threatening skin wounds. Studies of disease model cells have proven very informative in understanding the regulation and function of keratins in normal cells and have suggested new “pathway intervention therapy” approaches for treating still-incurable EBS.

Over a third of the world population is obese and thus at risk for Type 2 diabetes mellitus (T2DM). T2DM is associated with a plethora of skin diseases, such as impaired wound healing, dry and itchy skin, and Psoriasis. Yet, it remains unresolved whether diabetic skin complications are a direct consequence of impaired insulin/IGF-1 signaling (IIS) in the skin or occurs secondarily in response to metabolic alterations.

The skin epidermis provides a structural and innate immune barrier that protects the organism from outside challenges and water loss. We have identified crucial roles for epidermal IIS and lipid metabolism in epidermal morphogenesis and barrier function. We find that barrier dysfunction in morphogenesis leads to the induction of stress signaling to rescue barrier morphogenesis, whereas barrier defects in the adult evoke a morphogenetic barrier repair response followed by innate immune responses. Finally, we are linking epidermal IIS and barrier dysfunction to hyperglycemia and T2DM in mice and human.

The marks of humanity are omnipresent on Earth: we are in the Anthropocene. In turn, the multiple impacts on our environment increasingly question the values of a form of progress only driven by efficiency increments and optimization. What alternative path could we take? Many sustainable development solutions do not seem to depart from the “performance route”. Conversely, the prospect of degrowth does not mobilize either. Could biology offer a viable third way?

While some biological mechanisms certainly boast formidable efficiency, recent advances rather highlight the fundamental role of errors, incoherence or slowness in the development and the resilience of living organisms. In a fluctuating world, living beings are selected based on their robustness, not on their performance. Should our true nature consequently be considered suboptimal? To what extent could suboptimality become a counter-model to the credo of optimization and control in the Anthropocene? Why would suboptimality be relevant to skin sciences too?