Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation
- Int J Mol Sci. 2019 Apr 23;20(8):1991. doi: 10.3390/ijms20081991.
- 1. Lab of Cellular and Molecular Physiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy. [email protected].
- 2. Medical Scientist Training Program, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. [email protected].
- 3. Lab of Cellular and Molecular Physiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy. [email protected].
- 4. Division of Hematology, "A.O.U. Policlinico Vittorio Emanuele", University of Catania, 95123 Catania, Italy. [email protected].
- 5. Lab of Cellular and Molecular Physiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy. [email protected].
- 6. Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, 95123 Catania, Italy. [email protected].
- 7. Lab of Synthetic and Systems Biology, Department of Drug Sciences, University of Catania, 95123 Catania, Italy. [email protected].
- 8. Lab of Neurogenesis and Repair, Department of Drug Sciences, University of Catania, 95123 Catania, Italy. [email protected].
- 9. Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, 95123 Catania, Italy. [email protected].
- 10. Lab of Cellular and Molecular Physiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy. [email protected].
- 11. Lab of Neurophysiology, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy. [email protected].
Sonic Hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.
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