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Scarless healing: harnessing the wound healing potential of the oral mucosa


Institute of Dentistry

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Dr I Sequeira , Prof E O'Toole No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

This project would suit an ambitious and scientifically inquisitive individual with a clinical background. The project is designed to contribute to the global effort of creating a reference map of all the human cells, The Human Cell Atlas.

The student will be using single-cell RNA sequencing and state-of-art imaging techniques to investigate the regenerative potential of the oral mucosal tissues. It is an ambitious goal to generate a fundamental cell atlas for biomedical research and the clinical PhD student will be at the intersection between different disciplines, providing a fertile ground for new concepts and discoveries in regenerative medicine.

Introduction: Background and Significance
Wounds due to surgical incisions and due to injuries often do not heal and can result in complications such as slow healing, infections, inflammation and excessive scarring. Skin and periodontal surgery has long been associated with invasive protocols, including excision of soft tissues and post-operative scarring. Chronic wounds are a health problem that have devastating consequences for patients and cost the National Health Service £5 billion per annum [1]. Development of more efficient wound treatments is urgently needed to increase the quality of life of patients and to effectively reduce healthcare costs.

Wound healing is a complex process that requires overlapping phases of haemostasis, inflammation, proliferation and remodelling that in skin leads to scar formation [2]. Importantly, oral mucosa has more rapid wound healing and lacks scar formation [3–6]. Oral mucosal wounds re-epithelialise faster mainly due to differences in fibroblast proliferation and to lower levels of inflammation and angiogenesis when compared to wound repair in the skin [3,6]. In skin, it has been previously shown by transplantation assays and lineage tracing that the skin dermis has different fibroblasts subpopulations with different healing potential [7–9].

However, little is known about the mechanisms of scarless oral wound healing in oral epithelia. Differences were found in the expression of extracellular matrix components and the number of immune cells in oral wounds [10,11]. Recent work has shown that the oral mucosa has reduced differentiation and inflammatory response during wound healing and transcriptional analysis has suggested that Sox2 (expressed in oral epithelia) contributes to cutaneous wound healing inducing an expansion of the basal stem cell compartment of the skin in mice [12].
Hypothesis

Adult skin wounds are frequently accompanied by scar formation, that can become fibrotic. Oral mucosal wounds, however, heal in an accelerated fashion, displaying minimal scar formation. The mechanisms of scarless oral healing are yet to be revealed. Our aim is to investigate the healing capacity of oral mucosal wounds and apply its regenerative potential to enhance skin wound healing.

The student will do this by:
(1) generating a single-cell atlas of the human oral mucosal tissues using single-cell RNA sequencing to investigate the cellular heterogeneity of the oral mucosal tissue. For this, we will collaborate with the ‘Oral and Craniofacial Biology Network’ of the Human Cell Atlas Consortium (https://www.humancellatlas.org/learn-more/human-cell-atlas/) that will provide support for sequencing and computational analysis.
(2) exploring confocal and multiphoton imaging techniques to investigate the regenerative potential of the oral mucosal cell subpopulations ex-vivo and in-vivo.
The successful candidate must be a registered dental clinician in the UK.

Environment and supervision:
This project will benefit from the state-of-the-art facilities of the Institute of Dentistry and the Blizard Institute, supporting cutting-edge multi-disciplinary research. These include the Royal London Hospital (Barts Health Trust), the Genome Centre (QMUL), and the Imaging and Flow cytometry facilities in the Blizard Building, all located in Whitechapel.

This project will be involved and will contribute to the Human Cell Atlas project, determining the different cell types of the human body. Regular meetings with the ‘Oral and Craniofacial Biology Network’ will take place to optimise protocols and analysis pipelines, and curate different datasets from several labs.

We have assembled an experienced multi-disciplinary team to manage this project, with expertise in skin and oral biology, in imaging and transcriptomics, combining both clinical and basic research backgrounds (Dr Ines Sequeira, Institute of Dentistry (QMUL); Prof Edel O’Toole, Blizard Institute (QMUL); Human Cell Atlas project team).

How to apply
To apply, please click the 'institution website' button.

The successful candidate must be a registered dental clinician in the UK.

Funding Notes

The studentship will fund a student with a clinical qualification and GDC or both GDC/GMC registration at any career stage below consultant. They will be funded for three years at current, MRC rates. Studentships will include PhD fees (at home/EU levels) and up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.

References

[1] J. F. Guest et al., “Health economic burden that wounds impose on the National Health Service in the UK,” BMJ Open, vol. 5, no. 12, pp. 1–9, 2015.
[2] T. J. Shaw and P. Martin, “Wound repair at a glance,” J. Cell Sci., vol. 122, no. 18, pp. 3209–3213, 2009.
[3] L. Chen, Z. H. Arbieva, S. Guo, P. T. Marucha, T. A. Mustoe, and L. A. DiPietro, “Positional differences in the wound transcriptome of skin and oral mucosa,” BMC Genomics, vol. 11, no. 1, pp. 1–15, 2010.
[4] S. Enoch and P. Stephens, “Scarless healing: Oral mucosa as a scientific model,” Wounds UK, vol. 5, no. 1, pp. 42–48, 2009.
[5] H. Larjava, C. Wiebe, C. Gallant-Behm, D. A. Hart, J. Heino, and L. Häkkinen, “Exploring scarless healing of oral soft tissues,” J. Can. Dent. Assoc. (Tor)., vol. 77, no. C, pp. 1–5, 2011.
[6] J. E. Glim, M. Van Egmond, F. B. Niessen, V. Everts, and R. H. J. Beelen, “Chapter 2,” pp. 648–660, 2013.
[7] R. R. Driskell et al., “Distinct fibroblast lineages determine dermal architecture in skin development and repair,” Nature, vol. 504, no. 7479, pp. 277–281, 2013.
[8] C. Philippeos et al., “Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations,” J. Invest. Dermatol., vol. 138, no. 4, pp. 811–825, 2018.
[9] T. Tabib, C. Morse, T. Wang, W. Chen, and R. Lafyatis, “SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin,” J. Invest. Dermatol., vol. 138, no. 4, pp. 802–810, 2018.
[10] J. E. Glim, V. Everts, F. B. Niessen, M. M. Ulrich, and R. H. J. Beelen, “Extracellular matrix components of oral mucosa differ from skin and resemble that of foetal skin,” Arch. Oral Biol., vol. 59, no. 10, pp. 1048–1055, 2014.
[11] J. E. Glim, R. H. J. Beelen, F. B. Niessen, V. Everts, and M. M. W. Ulrich, “The number of immune cells is lower in healthy oral mucosa compared to skin and does not increase after scarring,” Arch. Oral Biol., vol. 60, no. 2, pp. 272–281, 2015.
[12] R. Iglesias-Bartolome et al., “Transcriptional signature primes human oral mucosa for rapid wound healing,” Sci. Transl. Med., vol. 10, no. 451, 2018.
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