A regenerative cartilage model for drug screening applications

New treatments for osteoarthritis have been limited by the lack cartilage tissue models that can accurately represent the in vivo environment needed for screening new treatments for therapeutic potential. A new 3D model for cartilage tissue has the potential to enable high-throughput screening, that can help identify treatment candidates with a higher chance of therapeutic success.

Professor Alicia El Haj and Dr Nicola Foster at the University of Birmingham are developing a new 3D model of cartilage tissue that can be used to test new treatments for osteoarthritis. Osteoarthritis is a degenerative joint disease that results from the breakdown of cartilage and is one of the leading debilitating diseases within the adult population. Damaged cartilage has limited capacity for self-repair, so there is an urgent need for new drugs and therapies that can delay the progression of osteoarthritis. At the moment, screening assays for new treatments are carried out in the lab using a single layer of cartilage cells. This 2D model does not accurately represent the cartilage structure and associated support cells that work together in the tissue microenvironment of a living joint. Therefore, many of the seemingly promising treatments identified using traditional assays in the lab do not lead to treatments that can be translated to the clinic for treating osteoarthritis.

The researchers have developed a 3D regenerative model of cartilage which maintains both mature and progenitor cells that make up cartilage in an arrangement that is spatially organised. The team then showed that this model could be transferred to a 96-well plate format, which is needed for screening candidate drugs in high-throughput assays. The model system allows the researchers to screen for new treatments that can induce the formation of cartilage.

The researchers are now exploring ways to scale-up this 3D model with liquid handling systems and automated imaging techniques so they can increase its throughput. The new 3D model is an exciting platform that holds great potential for high-throughput screening to identify drugs that can induce the formation of new cartilage, which can then be used to treat osteoarthritis.

The fate of lung stem cells: a 3D model for screening new drugs

Failure to repair damage to lung epithelia can lead to severe lung disease, and once this happens, there are no treatment options to reverse the damage or repair lung function. Activating stem cells in lung epithelium offers a promising approach for developing new therapies to tackle this problem but requires a deeper understanding of how cell fate decisions are regulated in airway epithelium.

Professor Sam Janes, Dr Yuki Ishii and Jessica Orr are developing 3D lung organoids that contain different cell types that make up lung epithelium tissue. These lung organoids will help the team study epithelial stem cell growth and differentiation under conditions that more closely resemble a living lung. Understanding what type of cell a stem cell will eventually differentiate into, and how this process could be manipulated using the right biochemical signals at the right time, is key to harnessing the power of stem cells to repair damaged tissue.

The team have already established a lab protocol for monitoring cell fate decisions in a 2D assay using a reporter gene system where differentiated cells can be identified and counted. They are now working on transferring this reporter gene system to the 3D lung organoids, so that the team can detect cell differentiation and understand the mechanisms that regulate it. Once this system is established, the team will use the lung organoids in a drug screen with 2,000 FDA-approved compounds, so that any positive hits (i.e. drugs that promote the differentiation of a lung stem cell into new lung epithelium cell) can be accelerated to the clinic.

These lung organoids will provide a valuable tool for identifying different drugs that can regulate stem cells in the lungs. This knowledge in turn can be applied for treating damaged lungs, for example a promising drug identified through this assay could repair damaged lung tissue by inducing stem cells to differentiate into new lung epithelial cells.

Case studies written by Dr Buddhini Samarasinghe, Science Writer, MRC

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