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-β 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-β 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.

LAM cells as potential drivers of senescence in ymphangioleiomyomatosis microenvironment / C. Bernardelli, S. Ancona, M. Lazzari, A. Lettieri, P. Selvaggio, V. Massa, C.C.G. Gervasini, F. DI MARCO, R. Chiaramonte, E.A. Lesma. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:(2022 Jun 24), pp. 7040.1-7040.18. [10.3390/ijms23137040]

LAM cells as potential drivers of senescence in lymphangioleiomyomatosis microenvironment

C. Bernardelli;S. Ancona;A. Lettieri;V. Massa;C.C.G. Gervasini;F. DI MARCO;R. Chiaramonte;E.A. Lesma
2022-06-24

Abstract

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-β 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-β 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.
senescence; LAM; mTOR; tuberin; SASP
Settore BIO/14 - Farmacologia
Settore MED/03 - Genetica Medica
Settore BIO/13 - Biologia Applicata
Settore MED/04 - Patologia Generale
Settore MED/10 - Malattie dell'Apparato Respiratorio
PSRL219SCENT_01 - Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2019) - CENTANNI, STEFANO - PSR_LINEA2_ / Piano di sviluppo di ricerca - Dotazioni dipartimentali - Linea 2 - 2019
PSRL220SCENT_01 - Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2020) - CENTANNI, STEFANO - PSR_LINEA2_ / Piano di sviluppo di ricerca - Dotazioni dipartimentali - Linea 2 - 2020
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/932471
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