Gamma-secretase inhibitors down-regulate the pro-fibrotic Notch signaling pathway in recessive dystrophic epidermolysis bullosa
Advances in tissue engineering and 3D bioprinting for corneal regeneration
16 January 2024
Beyond Vision: An Overview of Regenerative Medicine and Its Current Applications in Ophthalmological Care
17 January 2024

J Invest Dermatol. 2024 Jan 16:S0022-202X(24)00001-0. doi: 10.1016/j.jid.2023.10.045. Epub ahead of print. PMID: 38237731.

Gamma-secretase inhibitors down-regulate the pro-fibrotic Notch signaling pathway in recessive dystrophic epidermolysis bullosa

Authors: Angelo Giuseppe Condorelli 1Rebecca Nobili 2Anita Muglia 2Giorgia Scarpelli 2Elisa Marzuolo 2Cristiano De Stefanis 3Rossella Rota 4Andrea Diociaiuti 5Rita Alaggio 6Daniele Castiglia 7Teresa Odorisio 7May El Hachem 5Giovanna Zambruno 2

Affiliation:

  1. Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy;. Electronic address: agiuseppe.condorelli@opbg.net.
  2. Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy.
  3. Research Laboratories, Bambino Gesù Children’s Hospital, IRCCS, Viale di San Paolo 15, 00146 Rome, Italy.
  4. Department of Hematology and Oncology, Cell and Gene Therapy Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy.
  5. Dermatology Unit and Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165, Rome, Italy.
  6. Pathology Unit and Predictive Molecular Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165, Rome, Italy;; Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  7. Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167, Rome, Italy.

Abstract:

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the pro-fibrotic role of Notch pathway in different skin disorders, including RDEB. Here, we further investigated the role of Notch signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are up-regulated in primary RDEB fibroblasts (RDEB-FBs) as compared with controls, and their protein levels are further increased by TGF-β1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-FBs treated with PF-03084014 showed: (i) a significant reduction of contractility; (ii) a diminished secretion of TGF-β1 and collagens, and (iii) the down-regulation of several fibrotic proteins. Although less marked as compared to PF-03084014-treated cells, RDEB-FBs exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides new potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

Keywords: DAPT; JAG1; fibroblasts; nirogacestat (PF-03084014); skin fibrosis.

Download: https://www.sciencedirect.com/science/article/abs/pii/S0022202X24000010