MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis Giusy De Rosa, Claudia Russo, Silvia Garavelli, Dario Di Silvestre, Ilaria Spatocco, Giorgia Mele, Claudia La Rocca, Alessandra Colamatteo, Fortunata Carbone, Clorinda Fusco, Fabiana Passaro, Donatella Carpi, Elena Tagliabue, Francesco Prattichizzo, Francesca Brambilla, Pierluigi Mauri, Mirjam Hoxha, Valentina Bollati, Ilaria Giusti, Vincenza Dolo, Paola D’Antona, Paola Campomenosi, Valentina Mangolini, Annalisa Radeghieri, Paolo Bergese, Ivana Morabito, Alessandra Mandelli, Annamaria Finardi, Francesca Beretta, Edoardo Dalmato Schilke, Guido Cavaletti, Ettore Dolcetti, Fabio Buttari, Gianmarco Abbadessa, Simona Bonavita, Giacomo Lus, Elisabetta Signoriello, Roberta Lanzillo, Vincenzo Brescia Morra, Maria Mottola, Bruno Zuccarelli, Antonio Uccelli, Marco Salvetti, Diego Centonze, Roberto Furlan, Giuseppe Matarese, Claudio Procaccini, Paola de Candia Science Translational Medicine, 2025 CD4 + CD25 hi FoxP3 + regulatory T cells (T reg cells) are key controllers of immune self-tolerance, and their suppressive function is impaired in people with relapsing-remitting multiple sclerosis (pwRR-MS). Because the mechanisms underlying this condition are still ill-defined, we investigated the role of T reg cell–derived extracellular vesicles (T reg -EVs) in T reg cell dysfunction observed in pwRR-MS. We found that T reg -EVs from healthy individuals inhibit CD4 + conventional T (T conv ) cells by shuttling miR-142-3p from the T reg cell to the T conv cell. There, miR-142-3p down-regulated mRNAs necessary for T conv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11 . However, T reg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, T reg -EV miR-142-3p inversely correlated with the disability score and gadolinium-enhancing lesions in pwRR-MS. Together, our results elucidate a molecular mechanism involving miR-142-3p shuttled by T reg -EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.
Impairment of Renal and Hematopoietic Stem/Progenitor Cell Compartments in Frailty Syndrome: Link with Oxidative Stress, Plasma Cytokine Profiles, and Nuclear DNA Damage Silvia Bombelli, Chiara Grasselli, Paolo Mazzola, Valentina Veronesi, Ivana Morabito, Nicola Zucchini, Chiara M Scollo, Salvatore I Blanco, Sofia De Marco, Barbara Torsello, Federica Vitarelli, Laura Antolini, Cristina Bianchi, Valerio Leoni, Giuseppe Bellelli, Roberto A Perego Journals of Gerontology Series A Biological Sciences and Medical Sciences, 2024 Frailty is an age-related syndrome that drives multiple physiological system impairments in some older adults, and its pathophysiological mechanisms remain unclear. We evaluated whether frailty-related biological processes could impair stem cell compartments, specifically the renal stem compartment, given that kidney dysfunctions are frequent in frailty. A well-characterized in vitro nephrosphere model of human adult renal stem/progenitor cells has been instrumental to and was appropriate for verifying this hypothesis in our current research. Evaluating the effects of plasma from older individuals with frailty (frail plasma) on allogeneic renal stem/progenitor cells, we showed significant functional impairment and nuclear DNA damage in the treated cells of the renal stem compartment. The analysis of the frail plasma revealed mitochondrial functional impairment associated with the activation of oxidative stress and a unique inflammatory mediator profile in frail individuals. In addition, the plasma of frail subjects also contained the highest percentage of DNA-damaged autologous circulating hematopoietic progenitor/stem cells. The integration of both molecular and functional data obtained allowed us to discern patterns associated with frailty status, irrespective of the comorbidities present in the frail individuals. The data obtained converged toward biological conditions that in frailty caused renal and hematopoietic impairment of stem cells, highlighting the possibility of concomitant exhaustion of several stem compartments.
The cross-talk between Abl2 tyrosine kinase and TGFβ1 signalling modulates the invasion of clear cell Renal Cell Carcinoma cells Sofia De Marco, Barbara Torsello, Emanuela Minutiello, Ivana Morabito, Chiara Grasselli, Silvia Bombelli, Nicola Zucchini, Giuseppe Lucarelli, Guido Strada, Roberto A. Perego, Cristina Bianchi FEBS Letters, 2023 Clear cell Renal Cell Carcinoma (ccRCC) is the most common and metastatic urological cancer. Molecular players of ccRCC progression and metastasis are not completely known. Here, using primary cell cultures from patients' specimens, we found that TGFβ1/Smad signalling is more activated in high versus low grade ccRCC and inversely correlates with Abl2 tyrosine kinase protein expression. TGFβ1 treatment increased ubiquitination and degradation of Abl2 protein in ccRCC cell lines by TGFβ1/Smad pathway activation and reactive oxygen species production. 3D invasion and matrix degradation assays showed that Abl2 promoted TGFβ1‐induced ccRCC cell invasion and maturation of invadopodia, a hallmark of tumour invasion and metastasis. Our findings define Abl2 as a new downstream molecule of TGFβ1 signalling and putative target to counteract advanced ccRCC.
High glucose induces an activated state of partial epithelial-mesenchymal transition in human primary tubular cell cultures Barbara Torsello, Sofia De Marco, Silvia Bombelli, Ingrid Cifola, Ivana Morabito, Lara Invernizzi, Chiara Meregalli, Nicola Zucchini, Guido Strada, Roberto A. Perego, Cristina Bianchi Plos One, 2023 Tubulointerstitial fibrosis is observed in diabetic nephropathy. It is still debated whether tubular cells, undergoing epithelial-mesenchymal transition (EMT) in high glucose (HG) conditions, may contribute to interstitial fibrosis development. In this study, we investigated the phenotypic and molecular EMT-like changes and the alteration of inflammatory and fibrogenic secretome induced by HG in human primary tubular cell cultures. Taking advantage of this in vitro cell model composed of proximal and distal tubular cells, we showed that HG-treated tubular cells acquired a fibroblast-like morphology with increased cytoplasmic stress fibers, maintaining the expression of the epithelial markers specific of proximal and distal tubular cells. HG increased Snail1, miRNA210 and Vimentin mesenchymal markers, decreased N-cadherin expression and migration ability of primary tubular cells, while E-cadherin expression and focal adhesion distribution were not affected. Furthermore, HG treatment of tubular cells altered the inflammatory cytokine secretion creating a secretome able to enhance the proliferation and migration of fibroblasts. Our findings show that HG promotes an activated state of partial EMT in human tubular primary cells and induces a pro-inflammatory and pro-fibrogenic microenvironment, supporting the active role of tubular cells in diabetic nephropathy onset.
