Exploring the association between tissue stiffness and the migratory behaviour and biophysical properties of macrophage populations in endometriosis

Endometriosis is a medical condition where tissue like the lining of the uterus (endometrium) grows outside the uterus, forming 'lesions'. It affects about 190 million women worldwide and can cause chronic pelvic pain and infertility. The exact cause of endometriosis is still not fully understood. However, we know that certain immune cells called macrophages play a central role in how the disease develops and causes pain. Macrophages are highly adaptable cells that respond to signals in their environment. It is becoming clear that the type of macrophages present in diseased tissues, like endometriotic lesions, are different from the ones in healthy tissues. These 'disease-modified' macrophages in endometriosis can promote the growth of lesions, the growth of blood vessels into lesions, and the generation of pain. Endometriotic lesions are different from healthy endometrium. They have more fibrotic components, which means there's an abnormal build-up of connective tissue. The way cells move, change, and grow in the body is influenced not only by chemical signals but also by changes in the mechanical forces within tissues. In cancer, for instance, these mechanical changes can influence the development and spread of tumours. Interestingly, there are similarities between tumours and endometriotic lesions, including the activation of certain macrophages that promote tissue repair. Our previous research in a mouse model of induced endometriosis has shown that the macrophages in these lesions come from different sources. Some come from the normal uterine tissue, others large peritoneal macrophages that migrate into the lesions, and some are derived from circulating blood cells called monocytes. These different types of macrophages have varying effects on the development of endometriosis. Some are pro-disease, while others protect against development of lesions. There are still many gaps in our understanding of endometriosis. We don't know exactly how the mechanical properties of normal uterine tissue compare to the abnormal ectopic endometrial-like tissue (lesions) and how these differences affect the behaviour of macrophages. Additionally, we need to learn more about how these macrophages move and respond to different mechanical environments. We predict that lesions display altered ECM levels and stiffness which will impact the recruitment and behaviour of macrophages in lesions.
The aims of this research:
1.To quantitatively evaluate the level of ECM and stiffness of lesions: The student will compare the levels and organization of ECM components, particularly Collagen and quantitatively estimate the stiffness in the lesions (collected from a mouse model of induced endometriosis) with the surrounding peritoneal tissue and the normal uterine tissue.
2.To understand how tissue stiffness affects the recruitment and phenotype of macrophages in endometriosis: The student will correlate the Collagen levels and tissue stiffness with the number of and sub-populations of macrophages present in each tissue. They will also evaluate morphological characteristics of different populations of macrophages in vivo (cell and nuclear shape as well as cytoskeletal organization) in endometriosis lesions, peritoneal tissue and eutopic endometrium.
3.To understand how tissue stiffness might affect the behaviour of macrophages: The student will use ex vivo migration assays to investigate how monocytes and different sub populations of macrophages behave in response under different mechanical stimuli.
By studying these aspects, we hope to gain better understanding of the role of macrophages in endometriosis and potentially discover new ways to treat the condition.
This project sits firmly within the strategic priorities of 'mechanistic research to unlock the complexity of human health and disease' with a focus on 'reproductive health' and 'inflammation in relation to disease processes' within the remit of the population and systems medicine stategy