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Identification of different cell populations in cruciate ligaments of the murine knee joint and how they respond to injury

   Institute of Life Course and Medical Sciences

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  Prof E Comerford, Dr S Tew, Prof G Bou-Gharios, Dr B Poulet  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Ligaments are resilient connective tissues essential for bone-to-bone connections within joints. Breakdown of ligaments through acute injury, chronic disease or inflammatory insult leads to destabilisation of surrounding structures and the subsequent development of osteoarthritis (OA) with considerable social and economic costs.

Determining how the structure of ligament changes with injury and chronic disease such as OA is vital in preventing further damage and developing future therapies. However, there is a paucity of information about what specific cell subpopulations exist within ligament and their response to normal daily function, ageing and disease.

Ligaments are comprised of cells and extracellular matrix proteins such as collagen type I and proteoglycans. Cells isolated from mature ligaments are commonly termed ligamentocytes yet histological examination of ligament suggests a more heterogenous cell population. Collagen type I is organised into fascicles separated by an interfascicular space. Cells within fascicles tend to be flat and elongated compared to those in the interfascicular space which have a rounder morphology and are surrounded by proteoglycans such as aggrecan. A greater proportion of these rounded cells in human anterior cruciate ligaments has been associated with OA and ageing. Our observations of normal canine cruciate ligaments demonstrate that a higher proportion of rounded intrafascicular cells are found within tissue from breeds at low risk for ligament rupture. Cellular markers are not well described in ligament although there is evidence of expression of the putative tendon cell marker scleraxis in ligament cells. We have recently described important pathologies in knee ligaments in various models of murine osteoarthritis including hypertrophy of ligament cells and extracellular matrix modifications. Although the changes are clearly linked to abnormal mechanical input, the mechanisms involved in ligament degeneration at the cellular and molecular level remain largely unknown hindering our ability to block these deleterious changes

These observations suggest that there are subpopulations of cells within knee ligaments that may be associated with repair and regeneration. This project aims to determine cellular heterogeneity and to determine cell type specific transcriptional regulators within these tissues. We will define fundamental facets of ligament cell biology significantly enhancing our ability to investigate the molecular mechanisms regulating ligament health and disease.

It is our hypothesis that there is marked cellular heterogeneity in the cruciate ligaments in the knee joint and that certain cell types with specific transcriptomic markers with will respond differently to injury leading to ligament failure. This is important because failure of knee ligaments has been clearly implicated in the development of degenerative diseases such as osteoarthritis. However, we have a limited understanding of the biology of these tissues in regulating health and disease at a molecular and cellular level.

Aims & Objectives:

·        This project aims to define cellular heterogeneity in knee ligaments and to identify molecular markers of ligament cell types.

·        Cell populations will be identified microscopically in knee ligaments using adult transgenic mice specifically bred for determining specific cell types.

Our key goals include:

•            Identifying cell populations expressing fibroblastic, chondrocytic or tenogenic markers via a Cre recombinase-mediated shift from red to green fluorescence.

•            Examining how different cell populations are affected following mechanically induced injury and whether in vitro cell propagation methods commonly used in ligament research lead to an equal expansion rate of all cells or favour specific populations.

•            Sorting the in vitro expanded cells according to fluorescence and using transcriptional profiling to identify intrinsically retained phenotypic markers.

Other Training to be given:

As part of their degree registration, the student will have access to the Liverpool Doctoral College and its training resources including lectures on time management, team building, career development as well as thesis writing support and viva practice. Other modules such as study design and statistical training are available through the Department of Biostatistics at Liverpool. The student will be a member of the Comparative Musculoskeletal disease group at the Institute of Life Course and Medical Sciences. This research environment will provide a great opportunity for the PhD student to learn new skills in study design, participate in translational research, data analysis and preparing work for publication.

An Undergraduate Degree in Biological Sciences or related; 2:1 is required

Informal enquiries and expressions of interest to Professor Eithne Comerford on [Email Address Removed] or Dr. Blandine Poulet on [Email Address Removed]

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