Durham Doctoral Teaching Fellow: Investigation into the molecular mechanisms that govern age-related pigmentary changes in bioengineered human skin constructs in vitro

Pigmentary changes in skin tone, such as the development of “age spots” or solar lentigines are associated with an ageing phenotype and correlate with exposure to damaging ultraviolet radiation (UVR). The development of which is often unwanted and associated with poor physiological and sociological effects, particularly within an ageing global population. Through this project, we propose a means to recapitulate aspects of ageing-related pigmentary changes, utilising our well-characterised bioengineered pigmented skin construct (Gomez Front Med 2024) to include cells derived from an ageing donor population. Novel proof-of-concept data has been generated in this area, demonstrating the inclusion of ageing donor cells into both the epidermal and dermal compartments (Figure 1). The resultant skin constructs uniquely demonstrated pigmentary changes, most notably within the constructs that contained ageing cell populations, overall pigmentation was reduced and “age spots” were uniquely visible (1A), consistent with in vivo observations (1B). The aim of this project is to further develop and characterise an ageing pigmented skin platform, leading to an assay system capable of pre-clinical active screening and fundamental insights into the skin pigmentation ageing process at a cellular and molecular level.

Figure 1: Gross appearance of neonatal and ageing pigmented 3D in vitro full thickness skin models. (A) Gross appearance images in triplicate of neonatal, middle aged, and old aged pigmented full thickness skin models. (B) Appearance of age spots in vivo.

This project will utilize cutting edge technology in the form of human bioengineered pigmented skin equivalents developed by the group (Gomez Front Med 2024), combined with ageing cell populations to achieve a platform technology that will be applied to the following objectives: 

1.       Optimisation & Characterisation of Age-related Pigmented Constructs: The student will source commercially available cell lots that represent a variety of young and ageing donors, donor matched keratinocytes, melanocytes and fibroblasts. These cell types will then be incorporated into a pigmented skin construct to recapitulate age-related pigmentary changes such as the “age spot” phenotype described in Figure 1. A thorough morphological analysis will then be conducted to understand the structure and biologically processes present within hyperpigmented areas. This will include analytical techniques such as clinical skin tone measurements (ITA, melanin index), histology, keratinocyte proliferation measurements, skin complexion imaging, proinflammatory factor release and biomarker expression.

2.       Impact of Skin Tone on Age-related Pigmentary Changes: It is widely acknowledged that the incidence of “age spots” correlates with particular ethnicities and skin tones. To further understand this relationship, the optimised ageing pigmented skin construct will be adapted to incorporate melanocytes obtained from donors of varied skin tones, as we have previously demonstrated for neonatal constructs (Gomez Front Med 2024). In combination with UVR exposure, utilising specialist equipment available at Durham University (Goncalves Bioeng Trans Med 2022), the link between chronological, photoageing & skin tone will be explored, providing predictive data correlating with a diverse population. 

3.       Role of Pro-inflammatory Mediators in Age-related Hyperpigmentation: Previous research from the group has demonstrated a shift in the cytokine profile secreted by ageing dermal fibroblasts, resulting in increased secretion of pro-inflammatory factors (Costello J Cell Physiol 2024). The adoption of a senescence associated secretory phenotype (SASP) by ageing cells and the impact this has on bystander cells, is a widely accepted contributing factor to skin ageing. Given the link between inflammation and hyperpigmentation, this project will bridge the gap in our understanding of hyperpigmentation because of a pro-inflammatory state induced through mechanical insult or through an ageing cell population. This will provide an opportunity to advance our understanding of hyper-pigmentation, whilst elucidating points of intervention to attenuate the process.

4.       Interventions: Previously, we have demonstrated the hypo-pigmentary activity of Kojic Acid on our standard neonatal pigmented platform, along with other complexion enhancing molecules (Goncalves Bioeng Trans Med 2022). This aspect of the project will combine age-related pigmented constructs with known molecular actives to screen their ability at reducing the appearance of hyper-pigmented areas. This builds on the group’s experience in retinoid biology, active screening and established methods of topical delivery to ensure the student will receive a high level of support. Furthermore, this will produce an assay development providing measurable outputs to identify points of intervention to ameliorate unwanted age-related changes in complexion. 

The studentship is a Durham Doctoral Teaching Fellowship (DDTF). Successful candidates will pursue their research programme and also support the degree programme in Biochemistry/Biotechnology in the Department of Biosciences. The student will develop skills in tutorial delivery, academic support, and assist in the delivery of practicals. This opportunity will give the postgraduate student a diverse teaching and research portfolio.

The ideal candidate will have an undergraduate background in biosciences, independently or in combination with another discipline, preferably with biochemistry and/or biological chemistry knowledge.

This project is in competition with others for funding. Success will depend on the quality of applications received, relative to those for competing projects. If you are interested in applying, in the first instance contact the supervisor (Stefan Przyborski, stefan.przyborski@durham.ac.uk), with a CV and covering letter, detailing your reasons for applying for the project, by no later than 5th February 2025.