CE18 - Innovation biomédicale

A guided self-organized ASC multiorganoid as Advanced Medicinal Therapeutic Product for long-lasting reeducation of cell behavior and tissue function in age-related periodontal disease – PRISME

Submission summary

Prolongation of life expectancy is associated with an increase of age-related diseases (ARD). Most ARD exhibit multi-tissue disruptions leading to functional loss and patients’ quality of life impairment. Slow and subtle development of age-related tissue alterations delay diagnosis, resulting in poor conventional repair therapies prognosis. It is crucial to address these alterations as early as possible, when they remain local with slight tissue damage, and when regeneration potential is retained. These key elements highlight the need to identify appropriate therapeutic time window and 3D environment to optimize long-lasting therapy of aging tissue disruption. At a cell level, these lesions exhibit progressive impairment of mesenchymal stromal cells (MSC) subsets capacities to sustain homeostasis. This suggests they lose their properties to counteract permanent challenges to the organism with age, by loss of cellular network interactions coordination, thus failing to sustain tissue function over time. In that respect, characterization and determination of age-compromised MSCs subsets is the critical prerequisite for their long-term function reeducation both to prevent and reverse ARD lesions.
Based on their multiple trophic capacities and tissue repair critical steps control, adipose-derived MSCs (ASCs) therapy appears promising for the treatment of ARD lesion. The transient presence of grafted ASCs in tissue is consistent with their putative role as paracrine educator for native MSCs to monitor tissue integrity. Preclinical study from our laboratory provided encouraging evidence of a fibrin hydrogel containing dispersed ASC as Advanced Medicinal Therapeutic Product (ATMP) efficacy when grafted for the treatment of canine periodontitis, an age-related and disabling oral disease, affecting tooth-supporting tissues. Nevertheless, outcomes displayed inter-individual variability with incomplete regeneration and partial remaining inflammation, especially on oldest subjects. Thus, to improve ARD lesion cell therapy, ATMP graft have to provide primed ASC organized in a more adequate 3D microenvironment than fibrin hydrogels.
In this context, PRISME project aims to demonstrate the efficacy of multi-organoids based on guided self-organized ASCs in gelatin methacrylated (GelMa), displaying the suitable mechanical property modularity to enhance regeneration of lesions with the most complex morphologies, to support long-lasting rejuvenation of age-diseased periodontal tissues. The most important step is the in vivo trial in a particularly relevant spontaneous age-related periodontal disease mouse model used to point out that such microstructure providing ASCs in a customized environment graft is able to rejuvenate tissue by supporting endogenous MSC subsets reeducation. This model will be used for the first time in this application to emphasize the biological events involved in this ATMP tissue regeneration efficiency. To achieve this goal, we will use innovative molecular and histological approaches to describe the spectrum of age-dependent periodontal decline. This will allow to highlight the critical therapeutic time window, to identify the gingival dysfunctional MSC subsets signature, and the regenerative trajectory to reeducate them toward homeostasis. These data will support the pioneer operating process definition for a future translational approach in human. Based on our consortium members’ high-level competences that aggregate upon oral and aging medical considerations, our project combines multidisciplinary approaches to provide for the first time the opportunity to understand and draw key-concepts of an innovative cell therapy in an age-related pathology such as periodontitis.

Project coordination

philippe kemoun (RESTORE, a geroscience and rejuvenation research center)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

RESTORE RESTORE, a geroscience and rejuvenation research center
UFR Odontologie
LAAS-CNRS Laboratoire d'analyse et d'architecture des systèmes

Help of the ANR 537,135 euros
Beginning and duration of the scientific project: November 2022 - 36 Months

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