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Biomaterials with incorporated MSC-secreted PARAcrine molecules for bone reGENeration

Periodic Reporting for period 2 - PARAGEN (Biomaterials with incorporated MSC-secreted PARAcrine molecules for bone reGENeration)

Reporting period: 2019-03-20 to 2020-03-19

Regeneration of bone defects caused by trauma, resection of tumors, or metabolic bone diseases remains a critical challenge in orthopaedics. Mesenchymal stromal cell (MSC) therapy with biomaterials show huge promise for bone repair. After transplantation, MSCs can act as mediators of bone formation by the secretion of paracrine factors. Importantly, it appears that delivery of cells themselves may not be required for therapeutic benefit. When MSCs are cultured in vitro they release paracrine factors into their conditioned media (MSC-CM) including cytokines and extracellular vesicles. The scientific aim of the PARGEN project is to investigate the paracrine factors secreted by MSCs and their role in tissue regeneration. Specifically, these objectives included the exploration of the MSC secretome when cultured in various environments in vitro. The optimisation of the collection and isolation of MSC secreted factors was performed. MSCs cultured in vitro on calcium phosphates and the impact of these biomaterials on the healing capacity of the MSCs and the effects of the MSC secretome was investigated.Together these studies revealed that the culture microenvironment, in particular the mechanical properties and topography of MSC substrates greatly affects the secretion of factors by MSCs and in turn their impact on cells involved in bone tissue healing. These results have been disseminated through conference talks and seminars and will be presented in peer reviewed articles.
Towards the achievement of each of these objectives, significant research has been conducted. Briefly, the soluble (cytokines) and vesicular secretions (extracellular vesicles) of MSCs have been isolated and characterized. Significant work was performed to determine the optimal isolation method to achieve a pure population of extracellular vesicles from the conditioned media of MSCs. Further to this the cultured media for such collection was also optimized. The MSC paracrine secretions according to variations in the mechanical and chemical culture environments were evaluated. Methods to track EVs were explored and can permit uptake analysis as well as visualization of EV-biomaterial interactions. The functional effects of this MSC secretome on cells involved in healing and immune modulation were also investigated.
PARAGEN is uncovering MSC-secreted paracrine factors related to bone regeneration in various microenvironments. This project is immensely relevant to the EU community since there are one million bone regeneration procedures performed annually in Europe. The expected deliverables of this project will increase the knowledge base of the European scientific community as it focuses on some critically unanswered questions, namely, the most favorable environments for MSC-CM collections, and biomaterial interactions with MSCs and ensuing effects on the MSC secretome.
human Mesenchymal Stromal Cells