MSC in osteoarticular diseases : where do we stand?
Jorgensen1 on behalf of ADIPOA consortium
1 CHU Montpellier, Inserm U844. Hôpital saint-Eloi. 80, Rue Augustin Fliche. 34295 Montpellier, France.
Mesenchymal stromal cells (MSC) are adult stem cells exhibiting functional properties that have open the way for cell-based clinical therapies. Primarily, their capacity of multilineage differentiation has been explored in a number of strategies for skeletal tissue regeneration. More recently, MSCs have been reported to exhibit immunosuppressive as well as healing capacities, to improve angiogenesis and prevent apoptosis or fibrosis through the secretion of paracrine mediators including HGF, IL1RA, IL-6, PDL-1, TSG6, TGF-β1 and PGE2. In normal homeostasis, IL1Ra counterbalances the effect of IL1α and IL1β as a competitive receptor antagonist. MSC immunosuppressive effect is highly variable according to cell population heterogeneity.
We performed pre-clinical models of osteoarthritis, and showed that a local injection of ASC showed a reduction of synovitis, reduction of osteophytes, joint stabilization, reducing the score of cartilage lesions. We then investigated the role of iNOS, IL6 and IL1RA respectively using the inflammatory collagen-induced arthritis model. In contrast to wt MSCs, which reduced both the incidence and clinical signs of arthritis, IL1RA-/- MSCs were not able to prevent arthritis progression and even worsened the arthritic symptoms . µCT analysis showed a protection against bone erosion by wt MSCs but not in IL1RA-/- MSCs-treated mice . We found a decrease of the number of CD4+IFN-γ+ Th1 and CD4+IL-17+ Th17 lymphocytes in the spleens of wt MSCs-treated mice as compared to IL1RA-/- MSCs-treated mice. This work was completed by toxicology data showing the excellent tolerance of the local injection of ADSC and biodistribution showing the persistence of cells after 6 months in murine models.
We conducted a open-label phase 1 trial including 18 patients with severe osteoarthritis of the knee in failure of conventional therapies (62.5% were KL IV) at two sites, Montpellier and Wurzburg. Mean age was 61 years, with a 10 years history of knee OA. The patient received a single injection of autologous ASC 15 days after lipoaspiration (2.106 , 107 or 5.107) through intra-articular injection. The primary outcome measure of effectiveness was patient-reported WOMAC pain subscores by VAS in the affected knee at week 12. Secondary outcome measures included Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT OARSI) responses. We observed a decrease of the VAS Pain (73±11 mm day 0 to 32±23 month 3), and of WOMAC (50±18 to 25±7 month 3).
This study confirms the feasibility and safety of local injection of autologous cells from adipose tissue. Moreover, a molecular signature associated with increase immunosuppressive potential is described.
Pr. Christian Jorgensen, MD, PhD
Director of IRMB Institut de Recherche de Médecine Régénératrice et de Biothérapies
Head of Research Unit Inserm U 1183,
head of clinical unit for osteoarticular diseases and Department for Biotherapy at University Hospital CHU Lapeyronie University Hospital, Av G Giraud 34295 Montpellier France.
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Jeudi 25 janvier