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  The role of ageing cutaneous fibroblasts in modulating melanocyte pigmentation


   Faculty of Life Sciences

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The aim of the project is to gain an understanding of how aged skin fibroblasts and their secretory phenotype contribute to ageing pigmentation and commonly associated disorders.

Pigmentation disorders preferentially affect people of colour. Melanogenesis is regulated by paracrine factors secreted in a highly orchestrated manner from melanocytes and keratinocytes during UV radiation exposure, and when dysregulated can lead to hyperpigmentation (Bastonini et al., 2016). Pigmentation can be modified by several intrinsic and extrinsic factors including cutaneous ageing (chronologic and photoaging) and oxidative stress. Cellular senescence is thought to be one of the main drivers of an age-related phenotype and is associated with senile lentigo, changes associated with laxity and wrinkling (Coppé et al., 2010; Tchkonia et al., 2013; Kim et al., 2017). Senescent cells and those with the senescence-associated secretory phenotype (SASP) can be found in the epidermis (via sun-damage) and dermis of the skin during intrinsic and extrinsic ageing (Mine et al., 2008; Velarde and Demaria, 2016). Senescent fibroblasts chronically secrete matrix metalloproteinases that contribute to the degradation of collagen and other extracellular matrix components in dermal tissue, contributing to skin wrinkling (Fisher et al., 2002). It has been reported that an increasing proportion of senescent fibroblasts are found in aged, pigmented skin (Salducci et al., 2014; Kovacs et al., 2010), and whilst epidermal cells influence melanocyte regulation, few studies have looked at how ageing fibroblast factors contribute to age-related pigmentation changes. As SASP fibroblasts are known to have an altered secretory phenotype, which is inflammatory and have a higher reactive oxygen species (ROS) status (Abreu et al., 2021) , there could be key fibroblast-related mechanisms connected with skin ageing resulting in the dysregulated pigmentation seen in conditions such as, age-spots (solar lentigo), melasma and non-aged related hyper/hypopigmentary disorders (like post-inflammatory pigmentary anomalies).

The research project will be specifically designed using the methods below to answer multiple questions about the effect of ageing fibroblast environment on melanocyte biology and skin melanogenesis.

  1. Isolate/culture matched epidermal melanocytes and dermal fibroblasts from the scalp of multiple donors of varied age for co-culture, using different ages of replicative senescent fibroblasts with melanocytes and assess specific pigmentation gene/protein changes associated with the SASP phenotype using proteomics. Validate biomarker/targets in cells and in aged skin (qPCR, fluorescence, western blot). Investigate the correlation between dermal thickness, age and melanocyte number using antibody to the melanocyte-specific marker gp100, direct melanin staining and H&E.
  2. Construct full thickness 3D skin equivalent with aged fibroblast phenotype with melanocytes in the epidermis
  3. Apply ROS inducing agents (e.g. H2O2, UVR) to investigate higher stress susceptibility with ageing models. Changes in validated targets will be measured alongside stress markers, increased differentiation, and reduced proliferation. Melanin production/transfer to fibroblasts will be evaluated.
  4. Dr Farshid Sefat will aid development and testing of electrospun scaffolds for coating with agents to modulate the ageing response in 3D aged tissues such as antioxidants or other relevant molecules. Electrospun scaffolds can be embedded into 3D pigmented tissue models (as basement membranes) or applied to surface of 3D skin models to modulate melanocyte response or provide a protective effect in vitro. Student will assess delivery of agents from scaffolds and compare against other methods such as direct application on skin equivalent surface and measure penetration of compounds in 3D models.
  5. Measure the effects of specific light wavelengths (including UVR) on skin models and previously validated targets in aged cell/tissue models (+/- scaffolds). Student will travel to Prof Tobin’s lab in Dublin for a short period to look at the relative effects of specific light wavelengths (e.g., blue visible light) and/or UVR on cell models. Prof Tobin’s lab has specialist visible-wavelength light equipment to facilitate this.

We hypothesize this project will lead to evidence of melanocyte/fibroblast interactions through protein signalling allowing us to gain a better understanding of their influences on skin pigmentation biology. This could aid development of novel targets for pigment disorders such as vitiligo, hyperpigmentation, melasma and brown patches, and can be targeted for future research bids and KTP opportunities.

How to apply

Formal applications can be submitted via the University of Bradford web site. Applicants should register a new account and select 'Full-time PhD in Biomedical Science'.

Biological Sciences (4) Engineering (12)

Funding Notes

This is a self-funded project; applicants will be expected to pay their own fees or have access to suitable third-party funding, such as the Doctoral Loan from Student Finance. In addition to the university's standard tuition fees, bench fees also apply to this project.

References

Abreu,C.M., Reis, R.L. & Marques, A.P. (2021). Dermal papilla cells and melanocytes response to physiological oxygen levels depends on their interactions. Cell Proliferation, 54, e13013.
Bastonini, E., Kovacs, D. & Picardo, M. (2016). Skin pigmentation and pigmentary disorders: focus on epidermal/dermal cross-talk. Annals of dermatology, 28, 279-289.
Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.
Fisher, G.J., Kang, S., Varani, J., Bata-Csorgo, Z., Wan, Y., Datta, S. & Voorhees, J.J. (2002). Mechanisms of photoaging and chronological skin aging. Archives of dermatology, 138, 1462-1470.
Kim, Y.H., Choi, Y.W., Lee, J., Soh, E.Y., Kim, J.-H. & Park, T.J. (2017). Senescent tumor cells lead the collective invasion in thyroid cancer. Nature communications, 8, 1-14.
Kovacs, D., Cardinali, G., Aspite, N., Cota, C., Luzi, F., Bellei, B., Briganti, S., Amantea, A., Torrisi, M. & Picardo, M. (2010). Role of fibroblast‐derived growth factors in regulating hyperpigmentation of solar lentigo. British Journal of Dermatology, 163, 1020-1027.
Mine, S., Fortunel, N.O., Pageon, H. & Asselineau, D. (2008). Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: a new view of skin morphogenesis and aging. PLoS One, 3, e4066.
Salducci, M., André, N., Guéré, C., Martin, M., Fitoussi, R., Vié, K. & Cario‐André, M. (2014). Factors secreted by irradiated aged fibroblasts induce solar lentigo in pigmented reconstructed epidermis. Pigment cell & melanoma research, 27, 502-504.
Tchkonia, T., Zhu, Y., Van Deursen, J., Campisi, J. & Kirkland, J.L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of clinical investigation, 123, 966-972.
Velarde, M.C. & Demaria, M. (2016). Targeting senescent cells: possible implications for delaying skin aging: a mini-review. Gerontology, 62, 513-518.

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