Epigenetic control of stem cell activity during epithelial tissue regeneration

In the era of tissue engineering and the development of novel approaches for stem cell-driven organ regeneration, it is important for researchers and physicians to understand how multi-potent stem cells differentiate into specialized cell types, and why these processes are altered in pathological conditions, such as cancer, autoimmune conditions, impaired tissue regeneration, wound healing, hair loss.

Adult stem cells contribute to the regeneration process of many organs in a healthy organism. The mechanisms that control stem cell activity, however, are altered in many disorders. Research into the relationship between these disorders and the changed mechanisms is, thus, an important area for biomedical research.

Skin serves as an important source of adult stem cells, and several distinct adult somatic cell populations isolated from the skin were successfully employed for reprogramming and generation of induced pluripotent cells.

Research into genome and chromatin biology over the last two decades has revealed that in addition to genetic mechanisms, lineage-specific gene expression programs are also regulated epigenetically, i.e., via biochemical modification of the chromatin structure.

Polycomb group proteins are epigenetic regulators that operate as transcriptional repressors, compacting chromatin via enzymatic histone modifications and preventing binding of the transcription machinery to gene promoters. The polycomb group proteins play a critical role in the control of epithelial stem cell renewal and differentiation in the skin. Cbx4 as a member of Polycomb family of proteins protects epithelial stem cells from ageing in normal skin. However, its role in the control of stem cell activity during wound healing remains unclear.

This proposal represents a logical continuation of productive collaboration between two laboratories currently supported by the grants from the Medical Research Council UK, National Science Foundation of China and UK-China Science Bridge Programme. This proposal will extend these studies to define the role of Polycomb repressor Cbx4 in the control of stem cell activity in the skin during wound-induced regeneration.

Successful performance of this project will help in better understanding the complexity of regulatory mechanisms that control stem cell activity in regenerating epithelial tissues and in designing new approaches on how to target stem cells in the clinical conditions accompanied by their un-controlled activation/expansion or exhausting/loss.

Epigenetic mechanisms play an important role in the control of stem cell activity during development and regeneration. Understanding on how and why these mechanisms are altered in many disorders (cancer, autoimmune diseases, ageing, etc.) has become a growing priority in biomedical research.

This proposal represents a logical continuation of an existing collaboration between two laboratories funded by the grants from the MRC, NSFC and the UK-China Science Bridges Programme, which is focused on the analyses of roles of distinct epigenetic regulators in the control of stem cell activity during development and regeneration. This project will extend this successful collaboration and will study the role of Polycomb gene Cbx4 in the control of stem cell activity during wound-induced skin regeneration.

We will test the hypothesis that Cbx4 plays important roles in the control of gene expression programmes in adult epithelial stem cells during skin regeneration and:
1) Define whether the loss of Cbx4 activity in vivo will affect the self-renewing and differentiation potentials of skin epithelial stem cells and their progenies during wound healing;
2) Identify upstream regulators controlling Cbx4 expression in adult epithelial stem cells and their lineage-committed progenies.

Researchers from both labs will exchange knowledge relevant to their areas of expertise (skin/stem cell biology, molecular biology/epigenetics) and will share resources, data and ideas to generate data for large-scale joint grant proposals that will look at epigenetic regulation of stem cell activity in normal and diseased skin.

Success of this project will help in better understanding the complexity of regulatory mechanisms that control stem cell activity in regenerating epithelial tissues and in designing new approaches on how to target stem cells in the clinical conditions accompanied by their un-controlled activation/expansion or exhausting/loss.

Knowledge of the mechanisms regulating stem cell activity is highly important for improved understanding of the changes in organ regenerative capacity which occur during ageing and age-associated disorders, such as impaired wound healing and malignancy. This project will impact the following members of the community.

SCIENTIFIC COMMUNITY This project will provide substantial new knowledge for the scientific community and will contribute to an advance in public health benefits.
Delineating the functions of Cbx4 in skin regeneration will help to advance knowledge for investigators working in the following areas of fundamental research (developmental biology, molecular biology, stem cell biology and tissue regeneration, hair follicle biology), in addition to clinical (dermatology, gerontology) and veterinary medicine.

PUBLIC HEALTH & AWARENESS FOR UK AND CHINA
This project will have significant health implications and will benefit the public sector, including health professionals and their patients. There is an ever-increasing incidence of disorders with impaired stem cell activity within the UK, China and also within other countries, and the information generated by this project will provide new opportunities for therapeutic interventions to cure ageing-associated skin pathologies, including chronic epithelial wounds, skin cancers, specific forms of hair loss, which ultimately contributes to the enhancement of quality of life.

INDUSTRY
Business/industry will benefit from this project via advancement of the knowledge of molecular mechanisms controlling skin regeneration, which is clearly required for development of new approaches to improve diagnosis and for treatment of diabetic wounds and age-associated skin pathological conditions. Knowledge transfer activity with the industrial partners will be actively implemented for those areas of the results that can be used for new therapeutic product development. The new generated knowledge will also be used in relevant higher education courses for basic scientists and health professionals.

Overall, this project will provide information of substantial importance for researchers, the business/industrial sector, and health professionals within the NHS, whilst longer term will contribute to better public health.