3D-eMAGE

The aging of the bone tissue leads to dependency and frailty for many people around the world. Treatments, medical follow-up and care costs have a severe impact on the economic and social system. A great deal of research has therefore been carried out using in vitro and in vivo experimental models. However, the vast majority of these models are of murine origin. Although these models have provided some answers, there are limits imposed by species specificity and the need to use animal models in a rational way. In response to this challenge, we are proposing a new model for the study of bone tissue aging, based on a fully humanized model constructed from the cells from which it originates, mesenchymal stromal cells (MSCs). We have published and patented a culture protocol that produces very immature MSCs capable of self-organizing to form vascularized 3D spheroids with a structure close to that of the original tissue, therefore defined as organoids. Our results showed that from bone marrow (BM) MSCs, under these 3D conditions, it was possible to obtain structures whose organization and cellular composition were close to human BM and highly osteogenic. We also observed that bio-mechanical mechanisms could be similar to those observed during skeletogenesis. To consolidate this model, it is necessary to compare these organoids with the native BM as it exists in vivo in an extensive way, from transcriptomic experiments at the single-cell level to the study of epigenetism, which is strongly perturbed by aging processes. We will compare BMs from young people with BMs from the elderly. Going further, we will study the effects of senescent cells on organoids, as well as those of MSCs from rejuvenated human BMs. This will enable us to identify key molecules and molecular mechanisms involved in osteogenic aging. These molecules could serve as therapeutic targets or predictive biomarkers of bone diseases associated to aging. In addition, we will be looking at the effects of rejuvenated cells on senescent cells, and hence their beneficial anti-aging effects. This new model can also be used to screen pharmacological molecules, both in basic research and in regenerative medicine therapeutics. For this project, we have gathered internationally recognized research teams in the fields of human osteogenesis, stem cells, cell and tissue engineering, inflammaging, aging and senescent cell and their rejuvenation, and a transdisciplinary team with expertise in computational biology and bioinformatics.