A novel high-throughput screening platform identifies itaconate derivatives from marine Penicillium antarcticum as inhibitors of mesenchymal stem cell differentiation

• Main Authors: Marchese, Pietro, Mahajan, Nipun, O’Connell, Enda, Fearnhead, Howard, Tuohy, Maria, Krawczyk, Janusz, Thomas, Olivier P., Barry, Frank, Murphy, Mary J.
• Other Authors: Science Foundation Ireland, Marine Institute, Irish Research Council, College of Medicine, Nursing and Health Sciences, National university of Ireland Galway
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI 2020
• Subjects: marine fungi; high throughput screening; stem cell; regenerative medicine; drug discovery; Penicillium antarcticum; Antarc*
• Online Access: http://hdl.handle.net/10379/15998; https://doi.org/10.13025/21691; https://doi.org/10.3390/md18040192

Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair ectopic calcification. Bioactive small molecule discovery is critical to address ectopic tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort. Funding: This research was funded by Science Foundation Ireland Strategic Research Cluster, grant number 09/SRC/B1794. The Genomics and Screening Core facility at the National University of Ireland Galway is funded by NUIG and the Irish Government’s Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan 2007-2013. This research was partly funded by the Marine Institute under the Marine Research Program by the Irish Government, grant ...