Validation of a stem cell derived cartilage model for osteoarthritis research and drug screening

These research projects are in competition with 71 other studentship projects available across the GW4 BioMed MRC Doctoral Training Partnership. Up to 19 studentships will be awarded to the best applicants. Find out more information about the DTP including how to apply.

We have designed a method to produce tissue closely resembling articular cartilage from human stem cells.

Novel biophysical techniques will confirm similarities in matrix architecture and cellular differentiation, enabling its use in research on osteoarthritis development, identification of disease biomarkers and screening of therapeutic agents.

Osteoarthritis (OA) is a chronic, progressive joint disorder with 8 million sufferers in the UK alone. There is an urgent clinical need to:

  • better understand the mechanisms underlying disease development and progression
  • develop diagnostic assays for early identification and stratification of patients at risk of developing OA
  • streamline methods of drug screening.

Progress in all 3 areas requires realistic in vitro models.

Refined organotypic model

Our recent tissue engineering developments at Cardiff generates unrivalled cartilage tissue from chondrocyte progenitor cells (stem cells isolated from healthy human cartilage) in 35 days with properties of human cartilage (stratification into zones, matrix organisation and biomechanical integrity). Microscopic techniques at Exeter can explore biophysical properties of articular cartilage in unprecedented detail. This project unites these advances enabling microstructural characterisation of the model. Comparison with bovine/equine explants and healthy human tissue (available from clinical collaborators) will reveal culture period/loading regimen required to establish fully mature tissue, and inform modifications/refinements to culture protocols.

Cartilage responses in homeostasis

Cartilage matrix architecture differs between deep and superficial zones in line with cell differentiation, and cells are embedded in a highly specialised pericellular matrix. These factors impact profoundly on mechano and chemotransduction and must be replicated in a faithful model. Recent technological advances (Exeter) allow dynamic monitoring of these processes in situ. A unique combination of multiphoton microscopy with mechanical loading will investigate the mechanics of cartilage discs at a microstructural level. Raman spectroscopy will provide a position specific chemical signature of cell metabolism and matrix composition. Phases 1 and 2 will confirm suitability of the model as an experimental platform for cartilage research.

Modelling disease states

Mechanisms of early OA and OA progression will be explored (not currently feasible with available human tissue). Quantitative imaging with micromechanical testing, will dynamically track structural changes in collagen and elastin networks and in cell metabolism in 3D while the discs are:

  • loaded (mimicking physiological loads experienced by cartilage),
  • overloaded (non-physiological, injurious load),
  • treated with inflammatory mediators (such stimulation initiates an OA-like state in our model, replicating tissue breakdown in human OA).

We will introduce fluorescently tagged components into cells to access specific substructures of the matrix and, in the final part of the project, mutations in individual matrix components (using CRISPR/Cas9) to understand their effects on tissue functionality in unprecedented detail.

This cross-discipline project offers outstanding training opportunities and a unique set of skills including 3D cell culture models, molecular biology, state of the art microscopy techniques and Raman microspectrometery.

The model can be scaled-up to a high throughput biomarker discovery and pharmacological intervention screening system, so we anticipate the research will be of substantial interest to the research, clinical and pharmaceutical communities. Novel findings will be disseminated as appropriate through national/international meetings, publication and existing public engagement structures (ARUKBBC, CITER).

Supervisors

Dr Sharon Dewitt

Lecturer

Email:
dewitt@cardiff.ac.uk
Telephone:
+44 29207 44509

Programme information

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