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ERC

CiliaMechanoBio Report Summary

Project ID: 336882
Funded under: FP7-IDEAS-ERC
Country: Ireland

Mid-Term Report Summary - CILIAMECHANOBIO (Primary Cilium-Mediated Mesenchymal Stem Cell Mechanobiology in Bone)

Every 30 seconds a person suffers an osteoporosis-related bone fracture in the EU, resulting in significant morbidity, mortality, and health-care costs. Osteoporosis arises when mesenchymal stem cells (MSC) fail to produce sufficient numbers of bone forming osteoblasts. A key regulator of MSC behaviour is physical exercise, yet the mechanisms by which MSCs sense and respond to changes in their physical environment are virtually unknown. Primary cilia are ‘antennae-like’ sensory cellular extensions important in adult bone, but to date, their role in MSC behaviour is poorly understood. Therefore, the objective of this project is to determine the role of the stem cell primary cilium in exercise-induced bone formation. The identification of the cilium as central to stem cell behaviour will lead to the direct manipulation of MSCs via novel cilia-targeted therapeutics that mimic the regenerative influence of exercise. The achievements and outcomes of this project to date are summarised below.

Theme 1: In this theme we have developed novel bioreactors and fibrous materials that replicate the complex physical environment in the laboratory that the stem cell would experience within the body. Utilising these technologies we have demonstrated that the application of physical stimuli such as cyclic fluid shear and pressure to MSCs can induce bone formation in a laboratory setting. We are now exploring whether the primary cilium is required for this exercise-induced bone formation.

Theme 2: The objective of Theme 2 is to determine how the cilium is required for exercise-induced bone formation. To date we have shown that mechanically sensitive calcium channels, TRPV4 and PC2, and calcium inhibitable adenylyl cyclase 6, AC6, localise to the primary cilium of MSCs. Furthermore, we have shown that AC6 is required for MSCs to respond to mechanical stimuli and are currently exploring whether TRPV4 and/or PC2 are also required. Identification of the molecules involved cilia-mediated mechanosensing, will lead to the development of new cilia-targeted therapeutics to promote bone formation.

Theme 3: In this theme, we are investigating the role of the cilium in MSC recruitment. To date, we have demonstrated that low levels of Transforming Growth Factor β1 (TGFβ1) induce the recruitment of human MSCs and that this recruitment relies on proper formation of the primary cilium. Furthermore, we demonstrated that TGFβ signalling occurs at the ciliary base and subsequent translocation to the nucleus also relies on the proper formation of the primary cilium. These data demonstrate a novel mechanism of TGFβ signal regulation and recruitment in stem cells, and highlights the primary cilium as a potential therapeutic target to enhance MSC recruitment and bone formation.

Theme 4: Lastly in Theme 4 we are developing in-vivo models to specifically track and target MSCs. In particular, by specifically deleting the primary cilium and AC6 within the stem cell population we will be able to explore whether these cellular components are required for exercise-induced bone formation. Through the validation of our findings in these advanced models, we will be able to develop novel cilia-targeted therapeutics to enhance bone formation and treat osteoporosis.

Furthermore information on the achievements of this project can be found at http://www.mee.tcd.ie/biomaterials/People/DHoey.

Contact

David O'Shea, (Project Accounting Manager)
Tel.: +353 1 8962214
E-mail
Record Number: 191638 / Last updated on: 2016-11-21