Optimized chondrogenesis in an osteochondral defect model (VARIDON 2)

Background

Bone marrow derived stem (or stromal) cells (BMSCs) have been proposed a source of cells for autologous cell therapy. While showing promise in vitro, translation into the clinics has proven challenging. One reason for this is the inability to accurately predict cell function and hence, whether cells from a patient will behave in a predictable manner. In a previous AO funded study, we defined a TGF beta receptor ratio that was predictive of chondrogenesis. Furthermore, by relatively simple manipulation of the receptor ratio we could convert non-responsive donors and make them responsive to chondrogenic signals. Within this study, we aim to develop this techology further to improve chondrogenic differentiation within biomaterials with implant design in mind. Furthermore, we will activate chondrogenesis by way of multiaxial load, in an ex vivo endochondral defect model that more faithfully resembles a cartilage defect.

Effect of transient gene expression silencing on chondrogenic differentiation in non-responsive BMSCs. CTR positive shows the baseline chondrogenic differentiation ability; the use of siRNA against TGFBR2 and ACVRL1 dramatically improved differentiation, as shown by the formation of a glycosaminoglycan-rich matrix (Safranin O-Fast green staining).

Publication

Jahangir S, Eglin D, Potter N, Ravari MK, Stoddart MJ, Samadikuchaksaraei A, Alini M, Eslaminejad MB, Safa M. Inhibition of hypertrophy and improving chondrocyte differentiation by MMP-13 inhibitor small molecule encapsulated in alginate-chondroitin sulfate-platelet lysate hydrogel. Stem Cell Res Ther. 2020;11:436.

Basoli V, Della Bella E, Kubosch EJ, Alini M, Stoddart MJ. Effect of expansion media and fibronectin coating on growth and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells. Sci Rep. 2021;11(1):1308. https://doi.org/10.1038/s41598-021-92270-4

Armiento AR, Ladner YD, Della Bella E, Stoddart MJ. Isolation and In Vitro Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells. Methods Mol Biol. 2023;2598:65-73. https://www.doi.org/10.1007/978-1-0716-2839-3_6

Brose TZ, Ladner YD, Kubosch EJ, Stoddart MJ, Armiento AR. Co-culture of Human Articular Chondrocytes Seeded in Polyurethane Scaffolds and Human Mesenchymal Stromal Cells Encapsulated in Alginate Beads. Methods Mol Biol. 2023;2598:177-86. https://www.doi.org/10.1007/978-1-0716-2839-3_13
Presentation

Chen G, Basoli V, Guex AG, Stoddart M, Della Bella E. Improving chondrogenic potential of mesenchymal stromal cells by siRNA delivery in hydrogels. 2022 TERMIS EU (oral)

Della Bella E, Chen G, Mecchi L, Guex AG, Basoli V, Stoddart MJ. Improving chondrogenic potential of mesenchymal stromal cells by siRNA delivery in hydrogels. 2023 ORS (poster)