Generation of i-chondrocytes derived from iPS to repair cartilage defect – iREPAIR

Articular cartilage damage of the knee often occurs in young active people. It can result from trauma, repetitive injuries or inflammatory conditions. Patients often opt for surgery which aims to fill the cartilage lesion to not only restore joint function, but also to reduce the inconvenience of the untreated cartilage defects to progress to osteoarthritis (OA). Articular cartilage has a limited capacity for self-repair due to its complex structure, avascular nature, and low metabolic activities of chondrocytes. Current therapies for early OA include non-pharmacological and pharmacological approaches that have their own limitations, including drug leakage and severe systemic side effects, and provide only short-term relief of symptoms. Therefore, the development of cell-based cartilage tissue engineering strategies with chondroprogenitors, biological scaffolds and chondrogenic factors is a promising approach for long-term cartilage repair. Although mesenchymal stem cells (MSCs), widely studied and described for their chondrogenic potential, have shown clinical promise in patients, their heterogeneity at multiple levels as well as their tendency to lose multipotency, after isolation and expansion in vitro, hinder their efficacy and clinical transferability. To circumvent the heterogeneity of MSCs, MSCs derived from induced pluripotent stem cells (iMSCs) have been used. However, after chondrogenic differentiation, iMSCs, although to a lower degree than MSCs, show characteristics of hypertrophic chondrocytes. In this regard, the iREPAIR project aims to tackle one of the current challenges in the field of cartilage tissue engineering, which is to generate a suitable cell carrier for the controlled release of a chondrogenic inducer and to identify a homogeneous cell source that will result in functional chondrocytes with a stable phenotype. Neural crest cells (NCCs), which are involved in many, if not all, spontaneous regeneration processes in regenerative species, give rise during mammalian development to nasal chondrocytes that have been shown, in a clinical trial in 10 patients, to regenerate cartilage defects more efficiently than articular chondrocytes themselves.
Very recently, partner 1 has described the high cartilage regeneration potential of NCC-derived chondrocytes described by and partner 2 has demonstrated the ability of injectable collagen microspheres to act both as a cell support scaffold and as a reservoir for the long-term release of nucleic acid with adaptable release profiles. The present project, iREPAIR aims to generate an innovative biomedical product based on induced neural crest derived cells (iNCC) that will be seeded onto injectable collagen microspheres releasing chondrogenic a nucleic acid in a controlled manner. Thus, the specific objectives of the iREPAIR, are to: (i) generate an engineered universal iNCC able to produce mature and stable chondrocytes in vitro (iChondocytes) and (ii) produce the iREPAIR biomedicine to repair in vivo hyaline cartilage tissue.
To address these issues, iREPAIR will be organized in 3 work packages (WP): • WP1: Production of universal iNCC chondroprogenitors from iPS, • WP2: Generation of iChondrocytes and in vitro evaluation of their chondrogenic potential and • WP3: Proof of concept of the iChondrocyte chondroregenerative properties and iREPAIR chondrogenic potential. In case of success, iREPAIR innovative project will undoubtedly allow us to consider clinical trials and thus pave the way of new therapeutic avenues in the medical care of patients suffering of cartilage defects.