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Secretagogue effect of PDE4 inhibitor apremilast on human salivary gland organoids obtained from primary Sjögren’s syndrome patients
V. Manfrè1, S. Parisi2, I. Caligiuri3, O. Repetto4, A. Zabotti5, E. Pegolo6, C. Fabro7, S. De Vita8, V. Canzonieri9, C. Di Loreto10, F. Rizzolio11, L. Quartuccio12
- Division of Rheumatology, Department of Medicine, University of Udine, Italy.
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
- Division of Rheumatology, Department of Medicine, University of Udine, Italy.
- Institute of Pathology, Azienda Sanitaria Universitaria Friuli Centrale c/o Università degli studi di Udine, Italy.
- Division of Rheumatology, Department of Medicine, University of Udine, Italy.
- Division of Rheumatology, Department of Medicine, University of Udine, Italy.
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, and Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
- Institute of Pathology, Azienda Sanitaria Universitaria Friuli Centrale c/o Università degli studi di Udine, Italy.
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, and Department of Molecular Sciences and Nanosystems, Ca’Foscari University of Venice, Italy.
- Division of Rheumatology, Department of Medicine, University of Udine, Italy. luca.quartuccio@uniud.it
CER17159
2023 Vol.41, N°12
PI 2493, PF 2501
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PMID: 38149513 [PubMed]
Received: 23/09/2023
Accepted : 04/12/2023
In Press: 23/12/2023
Published: 23/12/2023
Abstract
OBJECTIVES:
The aim of the study was to culture vital salivary gland organoids obtained through labial or parotid biopsy of primary Sjögren’s syndrome (pSS) patients in order to evaluate their morphological and functional features in basal condition and after stimulation with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activator forskolin and phosphodiesterase 4 (PDE4) inhibitor apremilast, their in vitro regenerative capacity and the immune-histological resemblance with original tissue.
METHODS:
Salivary gland tissues from five pSS patients were processed to obtain vital organoids; swelling assay and cell proliferation tests were performed after forskolin and apremilast application. Immunochemistry evaluation on original salivary gland tissue and corresponding organoids was performed, and secretomics analysis was conducted to assess their functional status.
REULTS: After application of forskolin and apremilast, we observed organoid swelling after 30 minutes, compatible with a positive functional status and enhancement of saliva production. In 3 cases, apremilast induced organoid proliferation. All cases were positive for cytokeratin 14 (CK14) and most for cytokeratin 5 (CK5). All the cases were positive for amylase; its secretion, and thus functional status of organoids, was confirmed by its high concentration in the culture medium. A focal ductal differentiation was found in some cases, highlighted by epithelial membrane antigen (EMA) positivity. The more differentiated EMA positive areas were negative for the staminal marker CK14, showing a sort of “complementary staining”.
CONCLUSIONS. Our data highlighted that differentiated cells and vital functional organoids that recapitulate the development of original salivary glands can be obtained from pSS epithelium. For the first time, the direct stimulating effect of PDE4 inhibitor apremilast on pSS human salivary gland organoids is reported, opening new perspectives on targeting oral dryness with drugs that combine secretagogue and immunomodulatory effects.
