Regeneration and pathophysiology of joints

This team is composed of 31 people (22 full-time equivalent) including 13 senior researchers with Research Supervisor Qualifications (HDR). The team is headed by J. Guicheux and F. Blanchard as deputy head.

The REJOINT team is a translational and transdiciplinary team that focuses on the pathophysiology and aging of the joints from their basic aspects (cell fate, tissue modeling, senescence, autophagy, inflammation) to more applied aspects (rheumatoid arthritis, osteoarthritis, disc degenerative disease, osteochondral defects). The REJOINT team studies the fundamental processes of stem cell fate and differentiation during development and growth of cartilage and intervertebral disc. This team will also support the development of (i)
bio-inspired hydrogels for drug delivery systems and bioprinting, and (ii) strategies to exploit the properties of extracellular vesicles, mesenchymal or pluripotent stem cells for the regenerative medicine of cartilages and discs. To address this ambitious research program REJOINT is organized around 5 groups

Group 1 -  BIODIV: Stem cells and axial skeleton development

Leader: A. Camus

This theme involves 1 senior scientist (A. Camus-CR1 CNRS), 1 PhD Student (J. Warin), 1 engineer (C. Chédeville), 2 M2 students and 1 Postdoc researcher (to be hired).

Important questions in embryology and stem cell biology are when and how precursor cells are specified, differentiate along a specific lineage and acquire tissue-specilized functions. Today, our understanding of intervertebral disc (IVD) morphogenesis and cell phenotypes is far from complete. Our research focuses on the characterization of basic cellular and molecular mechanisms (gene regulation, growth factor control, cell-cell communication, cell-matrix interaction) that control the proliferation, differentiation and maturation of the notochordal cells, which are together precursors and regulators of the core of the IVD, where degenerative changes first take place. Our projects combine (i) fundamental studies using mutant mouse models, (ii) innovative human stem cells differentiation systems making use of 3D scaffolds with tunable physico-chemical properties mimicking relevant microenvironments, and (iii) transcriptomic approach and imaging analysis at the single cell level. Our major aim is to translate fundamental knowledge of developmental biology and morphogenesis to properly address the biological causes of disc degeneration and to inspire future regenerative strategies.

Group 2 - AGAIN: Aging and inflammatory joint diseases


Leader: F. Blanchard

This group involves 2 senior scientists (F. Blanchard DR2 Inserm, C. Vinatier MCU), 2 University/Hospital Professors (B. Le Goff PU-PH, C. Darrieutort PH), 2 PhD students (A. Defois, M. Georget), 3 engineers (N. Bon, J. De Lima, C. Boyer)

Aging is one of the main risk factors of osteoarthritis (OA) and paradoxically, the role of aging on chondrocyte senescence, autophagy, and alteration in metabolism are only partially known. Our main goals are (i) to explore the role of anti-geronic factors in articular cartilage aging and OA pathophysiology, (ii) to decipher the role of aging-associated senescence mechanisms in the appearance of OA, and (iii) to identify new molecules that target the autophagy/senescence balance.
Macrophages (MF) play a key role in the chronic inflammatory disease rheumatoid arthritis (RA), but the respective pathogenic role of the different MF subsets in RA is still unclear.  Our goals are (i) to better characterize synovial MF in early treatment-naive RA patients, (ii) to identify pathogenic inflammatory versus protective MF subsets, and (iii) bring the in vivo proof of concept that targeting specific subsets of MF may be of therapeutic potential in RA.

Group 3 - STRATOA: Immune cells and osteoarthritis personalized therapies

Leader: M.A. Boutet

This group involves 1 ATIP-Avenir junior group leader (M-A. Boutet), 1 PhD student (N. Gaigeard), and 1 postdoc (A. Cardon).

Osteoarthritis (OA) is a very heterogeneous disease driven by a large variety of factors, but this variability remains poorly considered in OA translational and clinical research. Importantly, OA synovial tissue presents significant changes, even before cartilage degradation. Synovitis has been correlated with OA severity and therefore represents a relevant target for therapeutic intervention. Our aims are (i) to characterize the synovial heterogeneity and define a relevant human and canine patients stratification, (ii) validate innovative tools to efficiently modulate innate immune cells, such as macrophages, for personalized treatment of OA, and (iii) understand the broader involvement of the immune system at both the local and systemic levels in the context of OA.

Main collaborators: C. Pitzalis and A. Nerviani, A. Mantovani and B. Bottazzi, I. Mattiola and A. Diefenbach

Group 4 - BIOMAX: Bio-inspired material concepts

Leader: V. Delplace

This theme involves 1 junior scientist (V. Delplace CRCN Inserm), 1 University/Hospital Professors (Y. Maugars) and 3 PhD students (M. Ambrosino, G Saint-Pe, L Terriac).

Biomaterials are now considered key elements in the success of innovative therapies and modeling approaches. In particular, researchers are progressively unravelling the major role of cell-material interactions on cell behavior, properties and fate. While it paves the way for material-guided therapies and advanced tissue engineering, it calls for the development of tunable material platforms and application-specific scaffold design. In the BIOMAX group, we are dedicated to tackling major challenges in the field of biofabrication and drug/cell delivery, with the development of innovative biomaterial concepts. Our research is centered on the use of new material chemistry tools for the design of "4-D bioinks", anisotropic materials, and mechanically resilient scaffolds, strongly inspired by the biological needs in the context of articular diseases.

Group 5 - HEAL: Hydrogels and joint translational research


Leader: C. Le Visage

This group involves 1 senior scientist (C. Le Visage DR2 Inserm), 8 University/Hospital Professors (G. Grimandi (PU-PH), Johann Clouet (PU-PH)), Marion Fusellier (MC ONIRIS), A. Hamel (PU-PH), K. Buffenoir (PU-PH), C. Decante (PHU), N. Bouhsina (MC Oniris), F. Nativel (AHU)), 1 research engineer (C. Boyer), 1 post-doctoral scientist (P. Humbert), and 1 PhD student (E. Carrot).

We develop injectable carriers of biologics for cartilage and intervertebral (IVD) regeneration, with an emphasis on i) paracrine effect of exogenous Mesenchymal Stem/stromal Cells (MSCs) and extracellular vesicles (EVs), and on endogenous repair using soluble molecules (cytokines, miRNA). The carriers include nano- and micro-sized alginate hydrogels (collab. INRAE, Nantes), electrospun fibers (collab.  IBMM, Montpellier), and lipid nanocapsules (collab. MINT, Angers). The efficacy of these different strategies is evaluated in vitro using human cell lines, or primary chondrocytes and disc cells. We recently set up an ex vivo culture of sheep IVDs, and we also develop a bioprinted model of IVD (collaboration AO Foundation, Switzerland) as an alternate ex vivo model. Evaluations are then conducted in various animal models (Vet school ONIRIS), with an emphasis on innovative imaging tools (MRI, microCT), before embarking on clinical trials (EU-H2020 IPSPINE project, Region DISCODOG project, ANR NEMESIS project).