Dottorato in Medicina e Terapia Sperimentale - Dynamic regulation of stem cell fate through materials properties
Academic year 2012/2013
- Degree course
- Ciclo XXV
- Teaching period
Sommario del corso
Mercoledì 19 giugno 2013
"Dynamic regulation of stem cell fate through materials properties"
Giancarlo Forte, PhD
Group Leader Cardiac Regeneration
Group International Clinical Research Center (ICRC)
Integrated Center of Cellular Therapy and Regenerative Medicine, St. Anne´s University Hospital Brno, Czech Republic
Local organization and contact:
Dr. Giovanni N. Berta
The homeostasis of the stem cell compartment within a given tissue is of outmost importance to guarantee the cellular turnover in the entire organ.
The nature of the biochemical, mechanical and structural cues concurring to maintain this equilibrium and selectively promote stem cell maturation when needed represents a topic of intense investigation.
Although the sensitivity of stem cells to substrate composition and mechanical cues has been demonstrated, the molecular processes allowing stem cells to sense mechanical signals arising from the ECM and turn them into a biological response still need full clarification.
Recent studies from independent research groups highlighted the role of two different pathways in sensing the mechanical properties and the nanotopography of the microenvironment. In particular, while Hippo pathway was indicated as a sensor machinery of the substrate mechanical composition, focal adhesion (FA) complex was deemed to be responsible of matrix nanotopography interpretation.
By employing thermo-responsive polymers displaying shape-memory properties, our group demonstrated that YAP and TAZ exert a crucial role in cardiac progenitor cell mechano-sensitivity and fate decision. In fact, cardiac progenitors respond to dynamic modifications in substrate rigidity and nanopattern by changing YAP/TAZ intracellular localization.
Through photo-activated micropatterned single cell arrays and materials having patho-physiological mechanical properties, we identified a novel activity for such proteins as regulators of cell migration on stiff and soft surfaces and highlighted a role for YAP/TAZ in cardiac progenitor cell proliferation and differentiation in response to mechanical or biological stimuli.
Furthermore we showed that YAP/TAZ expression is transiently triggered in the cardiomyocytes located in the infarct border zone, very likely as a response to the local changes in the nanotopography and mechanics of the ECM.
Moreover, an automated method based on confocal image analysis allowed us to quantify FA response to substrate composition in human mesenchymal stem cells.
In conclusion, our results, suggest a fundamental role for YAP/TAZ axis in regulating cardiac resident progenitor function in response to modifications in the mechanical and topological properties of the microenvironment. Together with the quantitative strategy proposed to study FA assembly, these data could help to define novel approaches to control cardiac progenitor cell fate by materials design.
Suggested readings and bibliography
Most Relevant and Recent publications:
1) Tam KV, Uto K, Ebara M, Pagliari S, Forte G, Aoyagi T. Mesenchymal stem cell adhesion but not plasticity is affected by high substrate stiffness. Sci Tech Adv Mater (2012). doi:10.1088/1468-6996/13/6/064205.
2) Forte G, Pagliari S, Ebara U, Uto K, Tam K, Romanazzo S, Escobedo-Lucea C, Romano E, Di Nardo P, Traversa E, Aoyagi T. Substrate stiffness modulates neonatal cardiomyocyte maturation in vitro. Tissue Eng part A (2012). 18: 1837-1848.
3) Romanazzo S, Forte G, Ebara M, Uto K, Pagliari S, Traversa E, Aoyagi T, Taniguchi A. Substrate stiffness affects skeletal myoblasts differentiation in vitro. Sci Tech Adv Mater (2012). doi:10.1088/1468-6996/13/6/064211.
4) Forte G, Pietronave S, Nardone G, Zamperone A, Magnani E, Pagliari S, Pagliari F, Giacinti C, Nicoletti C, Musaro’ A, Rinaldi M, Ribezzo M, Comoglio C, Prat M, Traversa E, Minieri M, Okano T, Di Nardo P. Human Cardiac Progenitor Cell Grafts as Unrestricted Source of Super-Numerary Cardiac Cells in Healthy Murine Hearts. Stem Cells (2011). 29: 2051-2061
5) Pagliari S, Vilela-Silva AC, Forte G, Pagliari F, Mandoli C, Vozzi G, Pietronave S, Prat M, Licoccia S, Ahluwalia A, Traversa E, Minieri M, Di Nardo P. Cooperation of Biological and Mechanical Signals in Cardiac Progenitor Cell Differentiation. Adv Mater (2011) 23: 514-518.