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Biomaterials with incorporated MSC-secreted PARAcrine molecules for bone reGENeration

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Investigating the bone healing capacity of molecules released by stem cells

Mesenchymal stem cells (MSCs) show huge promise for tissue regeneration, particularly mending defective bone. However, growing MSCs is a costly process that requires considerable expertise.

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Looking for a way to get round the lengthy procedure of growing MSCs, the PARAGEN project explored the potential of molecules, paracrine factors, secreted by MSCs. “The theory is they may be responsible for the therapeutic benefit of MSC transplantation,” explains Pierre Layrolle, project coordinator and principle investigator of the National Institute of Health and Medical Research, France.

Healing factors for bones secreted by stem cells

The PARAGEN team focused on testing molecules – cytokines – and secretions contained in bodies released by MSCs called extracellular vesicles (EVs). They also worked to optimise the methods used to collect these paracrine factors. Meadhbh Brennan, Marie Skłodowska-Curie fellow on the team relates: “We found that factors secreted by MSCs had immunomodulatory and tissue healing effects, specifically by promoting anti-inflammatory immune cell phenotypes and enhancing differentiation (development) of MSCs into bone-forming cells.” Not only that, but the secretions promoted angiogenesis, formation of blood vessels, in vitro and in vivo. These findings indicate the healing potential of the MSC secretome since resolution of inflammation, blood vessel development and osteoblast differentiation are all crucial for bone repair. Furthermore, when they cultured MSCs on calcium phosphate bone scaffolds of varying surface structure, they observed that their topography affects cytokine secretion by MSCs and, in turn, their impact on bone resorbing osteoclast cells. This has implications for tuning the MSC culture environment to generate an MSC secretome for the desired tissue healing applications.

Hurdles in the way of research progress overcome

“Distinguishing stem cell EVs from those already in the culture medium was a significant challenge,” says Brennan. The team had to perform extra work to determine the optimal culture and isolation technique to achieve a pure population of EVs from conditioned media of MSCs. “These optimisations were critical to effectively attribute functions to each portion of stem cell-derived secretions.” PARAGEN has gained a deeper understanding of the components of the MSC secretome and their effects on tissue repair. However, to achieve bone healing by the MSC secretome will require further exploration. Additional culture microenvironments, biomaterials to administer the MSC secretome, as well as optimising dosages will be investigated in future studies. Brennan summarises: “These results represent significant strides towards obtaining an off-the-shelf therapy that could harness the benefits of MSC therapy but circumvent the complex multi-step procedures involved with MSC implantation.”

Fast forward for future regenerative medicine research

As for the impact of the Marie Curie fellowship on Brennan’s research career, the benefits have been immense. “I have acquired new skills that I will be able to apply in a recently acquired faculty position in Biomedical Engineering and Regenerative Medicine at the National University of Ireland Galway with a co-appointment at the Schools of Medicine and of Engineering which will allow me to pursue a career in academic research,” she says. Her future research will focus on the characterisation of the MSC secretome. Brennan has also recently been awarded a European Research Council Starting Grant to pursue frontier research on the use of EVs for therapeutic benefit. She concludes: “I have garnered important academic collaborations through my Marie Curie fellowship which I will continue through future research partnerships alongside gaining new technical skills and experience of grant management and supervision of Masters and PhD students.”

Keywords

PARAGEN, MSCs, bone, secretome, EVs, stem cells, paracrine factors

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