Challenging dogma: an alternative non-hierarchical, epigenetically regulated model of the urothelium.
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Molecular Pathology
Abstract
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Planned Impact
Who could adopt or benefit from the research?
The immediate beneficiaries of our research will be the academic community but, in the long term, it is the public who will benefit from our research, which we recognise will need industry engagement to help with translation. Urinary incontinence is a major problem associated with ageing and there are numerous, poorly understood chronic age-associated conditions affecting the urinary bladder where a better understanding of the basic biology of the tissue and how it is regulated will revolutionise treatment. These conditions not only affect quality of life, but have a significant negative impact on society and the economy.
How will they benefit?
The results of this basic biology project will provide important insight that could help develop better cell and tissue engineering solutions as well as opening doors to rejuvenation therapies using epigenetic modulators:
1) The existence or not of a hierarchical stem cell is important for understanding whether the stem cell should be the primary target for therapies. This includes not only cancer, but poorly-understood chronic benign inflammatory conditions, such as interstitial cystitis, wherein there is an underlying failure of urothelial homeostasis.
2) there is a recognised need for new "tissue-engineered" approaches for patients with end-stage bladder disease. The results of the project will help inform strategy, such as whether to selected particular cell sub-population(s), or how to direct differentiation of induced pluripotent stem cells for therapeutic use.
3) Discovering how urothelial cell phenotypes are epigenetically-regulated will enable us to understand how environmental epigenetic modifiers compromise urothelial health (eg by disrupting plasticity) and how to reverse this by therapy. This could impact on environmental and health & safety practices.
4) in seeking regenerative therapies aimed at the chronic diseases of ageing, it is possible that epi-modifiers or epi-modulators could be used to "re-set" the epigenetic state of a diseased urothelium to re-establish normal homeostasis and regeneration.
The project is likely to generate knowledge and materials of interest to industry involved in delivering a) research tools to the life sciences and b) translation of regenerative medicine through to patient benefit. JS has substantial pharma industry contacts (including Astellas, Ono) with whom the potential of any research findings would be discussed under confidentiality agreement. Such an approach in the past has resulted in industry-funded research contracts and collaborations (eg through CASE studentships). Our tangible objective will be to actively engage with industry to generate a minimum of one CASE studentship or piece of contract research with industry directly from this research.
The immediate beneficiaries of our research will be the academic community but, in the long term, it is the public who will benefit from our research, which we recognise will need industry engagement to help with translation. Urinary incontinence is a major problem associated with ageing and there are numerous, poorly understood chronic age-associated conditions affecting the urinary bladder where a better understanding of the basic biology of the tissue and how it is regulated will revolutionise treatment. These conditions not only affect quality of life, but have a significant negative impact on society and the economy.
How will they benefit?
The results of this basic biology project will provide important insight that could help develop better cell and tissue engineering solutions as well as opening doors to rejuvenation therapies using epigenetic modulators:
1) The existence or not of a hierarchical stem cell is important for understanding whether the stem cell should be the primary target for therapies. This includes not only cancer, but poorly-understood chronic benign inflammatory conditions, such as interstitial cystitis, wherein there is an underlying failure of urothelial homeostasis.
2) there is a recognised need for new "tissue-engineered" approaches for patients with end-stage bladder disease. The results of the project will help inform strategy, such as whether to selected particular cell sub-population(s), or how to direct differentiation of induced pluripotent stem cells for therapeutic use.
3) Discovering how urothelial cell phenotypes are epigenetically-regulated will enable us to understand how environmental epigenetic modifiers compromise urothelial health (eg by disrupting plasticity) and how to reverse this by therapy. This could impact on environmental and health & safety practices.
4) in seeking regenerative therapies aimed at the chronic diseases of ageing, it is possible that epi-modifiers or epi-modulators could be used to "re-set" the epigenetic state of a diseased urothelium to re-establish normal homeostasis and regeneration.
The project is likely to generate knowledge and materials of interest to industry involved in delivering a) research tools to the life sciences and b) translation of regenerative medicine through to patient benefit. JS has substantial pharma industry contacts (including Astellas, Ono) with whom the potential of any research findings would be discussed under confidentiality agreement. Such an approach in the past has resulted in industry-funded research contracts and collaborations (eg through CASE studentships). Our tangible objective will be to actively engage with industry to generate a minimum of one CASE studentship or piece of contract research with industry directly from this research.
People |
ORCID iD |
| Andrew Feber (Principal Investigator) |
| Description | The funding provided through the BBSRC has afforded us the opportunity to generate multi-omic (transcriptomic, DNA methylation and chromatin accessibility) data from a unique set of urothelium populations. The datasets include: Paired bulk short read and long read (Oxford Nanopore Technologies) RNAseq of in situ isolated bladder (n=3) and ureter (n=3) urothelium. Bulk RNAseq of donor-matched (n=5; male) cultured and in vitro differentiated bladder and ureter urothelium to enable a comprehensive study of urothelium from different embryological derivations. Single cell transcriptomics on in situ-isolated human ureteric urothelium from 1) ureter (n=6) and 2) urinary bladder (transitional epithelium from dome region) (n=6 female). We have also generated single cell transcriptomic profiles from CD45-depleted, c-KIT immunoisolated cells from ureteric urothelium (n=3). ATAC-seq, to allow analysis of DNA accessibility, and genome wide DNA methylation profiling has been performed on a) in situ isolated urothelium (n=4 ureters); b) in situ isolated urothelium CD45-depleted then c-KIT immunoselected (n=4 ureters); c) NHU cells cultured in vitro as finite cell lines and prepared in matched proliferative and differentiated states (from n=6 ureters) and d) in situ isolated bladder urothelium (n=4 from dome of female bladders). Bulk ATAC-seq, RNA-seq, EPIC methylation array analysis has been performed on matched undifferentiated (in depleted medium) and differentiated cultures of NHU cells from ureter (n=4 cell lines) to investigate epigenetic regulation of urothelial differentiation. Bulk RNAseq of finite normal human urothelial cell lines in standard (n=3) and depleted (n=3) growth medium following defined nuclear receptor ligand activation to understand urothelial cell plasticity and regulation of differentiation. This data provides one of the most comprehensive analysis of urothelium to date, and will bring new insight and understanding to the biology of the urothelium. |
| Exploitation Route | Once we have collated and published our work, we expect our findings and the data to be used by scientists and clinicians with interests in development and pathogenesis of the urinary tract. |
| Sectors | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |