Regeneration and pathophysiology of joints

This team is composed of 30 people (24 full-time equivalent) including 10 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

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) and a M2 student.

An important question in embryology and stem cell biology is when and how precursor cells are specified and differentiate. Today, our understanding of intervertebral disc (IVD) morphogenesis is far from complete. We also have a limited knowledge of the controlling signalling pathways, transcriptional regulators and morphogens implicated in disc differentiation at each developmental stage and during growth and maturation. A more in-depth understanding of the cellular and molecular mechanisms of intervertebral disc development is however a prerequisite to properly address the biological causes of disc degeneration and develop innovative regenerative strategies for the IVD.


Group 2 - AGAIN: Aging and inflammatory joint diseases

AGAIN

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
STRATOA

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

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
Biomax

This theme involves 1 junior scientist (V. Delplace CRCN Inserm), 1 Hospital Professor (Y. Maugars, PU PH), 1 post-doctoral fellow (P. Tournier), and 2 PhD students (N. Lagneau, M. Ambrosino).

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

HEAL

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)), 2 post-doctoral scientists (S. Grastilleur, 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 incude nano- and micro-sized alginate hydrogels (collab. INRAE, Nantes), electropsun fibers (collab.  IBMM, Montpellier) and lipid nancapsules (collab. MINT, Angers). Efficacy of these different strategies are 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. Evaluation are then conducted in various animal models (Vet school ONIRIS), with an emphasis on innovative imaging tools (MRI, microCT), before embarking in clinical trials (EU-H2020 IPSPINE project, Region DISCODOG project).