Ranzoni, A; (2018) Bone repair potential of human amniotic fluid stem cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The amniotic fluid is a rich source of fetal mesenchymal stem cells with broad differentiation capacity. Human amniotic fluid stem cells (AFSCs) have a high expansion potential, fast growth kinetics and harbour therapeutic potential to treat a variety of conditions. Moreover, they are easily isolated at mid-trimester or at delivery and can be used without ethical restrictions. Osteogenesis imperfecta (OI) is a genetic disease characterised by bone fragility, due to production of abnormal collagen type I. In this study, human AFSCs were transplanted into immunocompetent oim mice (OI mouse model, n=28) at birth. Bones were harvested after 8 weeks and analysed for mechanical properties, micro-structure, engraftment of donor cells and gene expression. Non-transplanted oim and wild-type mice were used as controls. Human AFSC injection decreased bone fracture rate and increased bone strength. Donor cells migrated to the bones, engrafted into sites of active bone formation and appeared to differentiate into osteoblasts, producing normal collagen. Moreover, transplantation improved the microarchitecture of the bones, although bone volume remained unaffected. Transplantation also promoted endogenous osteogenesis, with mouse genes involved in osteoblast differentiation and skeletal development significantly up-regulated, compared to non-transplanted mice. As a side project, a protocol for the isolation and differentiation of human fetal osteoblasts from the calvaria was optimised and a biobank of 24 samples, from gestational ages ranging from 9 to 21 weeks post-conception, was established. The data presented in this thesis indicate that human AFSCs are a promising source for cell therapy in OI. Donor cells may exert their therapeutic effects both by normalising the ECM and by influencing the maturation of resident osteoblasts. Ongoing work is focused on the further understanding of the mechanism of action of donor cells, using co-culture experiments with human AFSCs and human fetal osteoblasts.

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