MECHANOBIOLOGY OF DISEASE

Investigating the mechanics of life and disease

Giancarlo Forte, Ph.D.

  • We provided evidence that mechanosensitive protein YAP contributes to cell-matrix interaction by directly promoting the transcription of focal adhesion genes. This result is relevant for a number of physiological and pathological processes.
  • We generated the first nanoscale 3D map of human heart pathological remodeling and identified mechanosensitive protein YAP as key player in this process.
  • We gave the proof of concept that tampering with mechanosensitive pathways can be exploited to control the adipogenic drifting of cancer cells, thus inhibiting their proliferation and dissemination.

Research focus
The Mechanobiology of disease (MBD) team is mainly interested in correlating defects in tissue-speci­fic cell mechanobiology system with the onset of aging pathologies with and a specific focus on those affecting the cardiovascular system. The working hypothesis of MBD is that defects in the function of the apparatus cells use to perceive and respond to external mechanical cues – the mechanosensing appara­tus – which contributes to aging-associated pathologies.

MBD researchers adopt loss- and gain-of-function approaches, microfluidics and micropatterning techno­logies to manipulate the mechanosome of adults, pluripotent stem cells and stem cell-derived cardiac ce­lls. MBD takes the advantage of cutting-edge technologies for live imaging, cell separation and high-throu­ghput gene and protein analysis to highlight perturbations in the mechanosensing apparatus occurring in the cardiac tissue and cells derived from patients.

Research objectives
• Identification of potential cellular mechanosensors involved in the onset of aging pathologies and suitable as bio-markers of the diseases.
• Identification of novel molecular processes involved in contractile phenotype acquisition.
• Generating valuable in vitro models of aging diseases.

Main partners

  • University of Porto, Porto, Portugal
  • Katholieke Universiteit Leuven, Belgium
  • University Campus Bio-Medico, Rome, Italy
  • University of Trieste Italy
  • University of Melbourne, Australia

Offered services and expertise

  • Multicolor high quality confocal imaging.
  • Live imaging in confocal microscopy.
  • 3D confocal rendering.
  • Automated MACS cell separation.
  • Real Time PCR and PCR arrays.
  • Multiphoton analysis of thick biological tissues.

Top publications

  • Nardone G, Oliver De La Cruz J, Vrbsky J, Martini C, Pribyl J, Skládal P, Pešl M, Caluori G, Pagliari S, Martino F, Maceckova Z, Hajduch M, Sanz-García A, Pugno NM, Stokin GB, Forte G. YAP regulates cell mechanics by controlling focal adhesion assembly. Nat Commun (2017) doi:10.1038/ncomms15321.
  • Perestrelo AR, Silva AC, Oliver-De-La-Cruz J, Martino F, Horváth V, Caluori G, Polanský O, Vinarský V, Azzato G, de Marco G, Žampachová V, Skládal P, Pagliari S, Rainer A, Pinto-do-Ó P, Caravella A, Koci K, Nascimento DS, Forte G. Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart. Circ Res (2020) DOI: 10.1161/CIRCRESAHA.120.317685.
  • Pagliari S, Vinarsky V, Martino F, Perestrelo AR, Vrbsky J, Oliver-De-La-Cruz J, Caluori G, Skladal P, Zampachova V, Kytyr D, Grassi G, Sampaolesi M, Rainer A, Forte G. YAP-TEAD control of human pluripotent stem cell mechanics guides cardiogenic mesoderm specification. Cell Death Differ (2020) DOI:10.1038/s41418-020-00643-5.
  • Oliver-De La Cruz J, Nardone G, Vrbsky J, Pompeiano A, Perestrelo AR, Capradossi F, Melajová K, Filipensky P, Forte G. Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading. Biomaterials (2019) doi: 10.1016/j.biomaterials.2019.03.009. I
  • Mosqueira D, Pagliari S, Uto K, Ebara M, Romanazzo S, Escobedo-Lucea C, Nakanishi J, Taniguchi A, Franzese O, Di Nardo P, Goumans MJ, Pinto-do-Ó P, Aoyagi T, Forte G. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano (2014) 8: 2033-2047.

Other selected results

  • Identification of YAP protein as the key determinant of cell-ECM interaction.
  • Identification of YAP protein as a novel marker in myocardial infarction.
  • Identification of HGF as a factor involved in MSC differentiation.
  • Generation of human cardiac progenitor cell patches for myocardial infarction treatment.