{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:53:05Z","timestamp":1784829185963,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AiLAM Onlus (Associazione Italiana LAM)","award":["RV_LIB16_M"],"award-info":[{"award-number":["RV_LIB16_M"]}]},{"name":"AiLAM Onlus (Associazione Italiana LAM)","award":["LIB_VT17"],"award-info":[{"award-number":["LIB_VT17"]}]},{"name":"AiLAM Onlus (Associazione Italiana LAM)","award":["PSR Linea 2 PSR2019_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2019_DIP_013"]}]},{"name":"AiLAM Onlus (Associazione Italiana LAM)","award":["PSR Linea 2 PSR2020_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2020_DIP_013"]}]},{"name":"ST Associazione Sclerosi Tuberosa","award":["RV_LIB16_M"],"award-info":[{"award-number":["RV_LIB16_M"]}]},{"name":"ST Associazione Sclerosi Tuberosa","award":["LIB_VT17"],"award-info":[{"award-number":["LIB_VT17"]}]},{"name":"ST Associazione Sclerosi Tuberosa","award":["PSR Linea 2 PSR2019_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2019_DIP_013"]}]},{"name":"ST Associazione Sclerosi Tuberosa","award":["PSR Linea 2 PSR2020_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2020_DIP_013"]}]},{"name":"Universit\u00e0 degli Studi di Milano","award":["RV_LIB16_M"],"award-info":[{"award-number":["RV_LIB16_M"]}]},{"name":"Universit\u00e0 degli Studi di Milano","award":["LIB_VT17"],"award-info":[{"award-number":["LIB_VT17"]}]},{"name":"Universit\u00e0 degli Studi di Milano","award":["PSR Linea 2 PSR2019_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2019_DIP_013"]}]},{"name":"Universit\u00e0 degli Studi di Milano","award":["PSR Linea 2 PSR2020_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2020_DIP_013"]}]},{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano\u201d","award":["RV_LIB16_M"],"award-info":[{"award-number":["RV_LIB16_M"]}]},{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano\u201d","award":["LIB_VT17"],"award-info":[{"award-number":["LIB_VT17"]}]},{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano\u201d","award":["PSR Linea 2 PSR2019_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2019_DIP_013"]}]},{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano\u201d","award":["PSR Linea 2 PSR2020_DIP_013"],"award-info":[{"award-number":["PSR Linea 2 PSR2020_DIP_013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Senescence is a stress-response process characterized by the irreversible inhibition of cell proliferation, associated to the acquisition of a senescence-associated secretory phenotype (SASP), that may drive pathological conditions. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells, featuring the hyperactivation of the mammalian Target of Rapamycin Complex 1 (mTORC1) for the absence of tuberin expression, cause the disruption of the lung parenchyma. Considering that LAM cells secrete SASP factors and that mTOR is also a driver of senescence, we deepened the contribution of senescence in LAM cell phenotype. We firstly demonstrated that human primary tuberin-deficient LAM cells (LAM\/TSC cells) have senescent features depending on mTOR hyperactivation, since their high positivity to SA-\u03b2 galactosidase and to phospho-histone H2A.X are reduced by inducing tuberin expression and by inhibiting mTOR with rapamycin. Then, we demonstrated the capability of LAM\/TSC cells to induce senescence. Indeed, primary lung fibroblasts (PLFs) grown in LAM\/TSC conditioned medium increased the positivity to SA-\u03b2 galactosidase and to phospho-histone H2A.X, as well as p21WAF1\/CIP1 expression, and enhanced the mRNA expression and the secretion of the SASP component IL-8. Taken together, these data make senescence a novel field of study to understand LAM development and progression.<\/jats:p>","DOI":"10.3390\/ijms23137040","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"7040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["LAM Cells as Potential Drivers of Senescence in Lymphangioleiomyomatosis Microenvironment"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3813-9038","authenticated-orcid":false,"given":"Clara","family":"Bernardelli","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1999-129X","authenticated-orcid":false,"given":"Silvia","family":"Ancona","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5927-2965","authenticated-orcid":false,"given":"Melania","family":"Lazzari","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-0423","authenticated-orcid":false,"given":"Antonella","family":"Lettieri","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"},{"name":"\u201cAldo Ravelli\u201d Center for Neurotechnology and Experimental Brain Therapeutics, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-7122","authenticated-orcid":false,"given":"Piera","family":"Selvaggio","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-9515","authenticated-orcid":false,"given":"Valentina","family":"Massa","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"},{"name":"\u201cAldo Ravelli\u201d Center for Neurotechnology and Experimental Brain Therapeutics, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1165-7935","authenticated-orcid":false,"given":"Cristina","family":"Gervasini","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"},{"name":"\u201cAldo Ravelli\u201d Center for Neurotechnology and Experimental Brain Therapeutics, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1743-0504","authenticated-orcid":false,"given":"Fabiano","family":"Di Marco","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"},{"name":"Respiratory Unit, Azienda Socio Sanitaria Territoriale-Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1078-1704","authenticated-orcid":false,"given":"Raffaella","family":"Chiaramonte","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9096-713X","authenticated-orcid":false,"given":"Elena","family":"Lesma","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of Cellular Senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/bjc.2016.115","article-title":"Context-dependent effects of cellular senescence in cancer development","volume":"114","author":"Lecot","year":"2016","journal-title":"Br. 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