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Title: Novel effects of bisphosphonates on stem cells and tissue regeneration
Author: Misra, Juhi
ISNI:       0000 0004 5916 1407
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2015
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The integrity of most tissues is highly dependent on resident self-renewing stem cells, which are vulnerable to DNA damage due to physical and chemical insults thus compromising their repopulation capacity and maintenance of tissue integrity. Examples include accumulation of DNA damage with age or following radiotherapy and chemotherapy in cancer patients. Interventions that can reduce accumulation of DNA damage in normal stem cells and maintain tissue integrity may improve patient survival and quality of life. Reports on a robust but unexplained reduction in mortality in osteoporotic patients treated with zoledronate pointed to the question whether this effect was associated with an extension in stem cells' lifespan due to reduced accumulation of DNA damage. To test this hypothesis, human mesenchymal stem cells (hMSC, progenitors of osteoblast) that are known to undergo cellular ageing were used as a model. Indeed, zoledronate extended hMSC lifespan and this was associated with reduced incidence of DNA double strand breaks. Pre-treatment with zoledronate followed by ionizing radiation also resulted in enhanced DNA repair with extended lifespan of hMSC compared to both irradiated and non-irradiated hMSC used as controls. It also significantly increased their clonogenic and differentiation ability compared to untreated controls. Moreover, administration of zoledronate in C57Bl/6 mice exposed to irradiation significantly reduced the loss of surviving MSC following whole body irradiation. In a model of zebrafish, zoledronate enhanced tail regeneration following irradiation and amputation. All these effects were mediated by inhibition of the mevalonate pathway and of the mammalian target of rapamycin (mTOR) signalling. These effects were not restricted to hMSC. Zoledronate had similar effects in other stem cell types, such as the murine intestinal stem cells (ISC). Irradiation resulted in a significant reduction in the number of leucine-rich G-protein coupled receptor-5 (LGR5) ISC; however, this was rescued by administration of zoledronate prior to irradiation. Moreover, a significant reduction in accumulation of DNA damage foci was observed in LGR5 cells in mice treated with zoledronate prior to irradiation compared to irradiated controls and this resulted in preserved tissue integrity, preventing radiation induced mucositis, an important side effect of radiotherapy in cancer patients. Interestingly, zoledronate had differential action in cancer cells. Following irradiation, zoledronate was unable to enhance repair of DNA damage in myeloma, breast and prostate cancer lines and when combined with irradiation, zoledronate treatment resulted in significant decline in their clonogenic ability. In conclusion zoledronate protected normal stem/progenitor cells (both mesenchymal and intestinal) from accumulation of DNA damage due to ageing and irradiation via mTOR signalling and had differential action in cancer cells. Given the good safety profile of zoledronate, this drug offers new therapeutic opportunities in cancer and ageing which may be readily exploited.
Supervisor: Bellantuono, Ilaria ; Russell, Graham Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available