Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino (Torino, 28 novembre 2013).
Oggi nel Salone del Rettorato, il Rettore dell'Università degli Studi di Torino, Prof. Gianmaria Ajani, e il Responsabile Emea LA di Fresenius Medical Care, Prof. Emanuele Gatti, hanno firmato la Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino per la produzione di cellule staminali finalizzate alla terapia dell'insufficienza renale ed epatica.
ABCD 2014 - Associazione di Biologia Cellulare e del Differenziamento - Premio "Joint National Ph.D. Meeting" - (Pesaro, 10-12 ottobre 2013). Miglior presentazione orale.
Letizia De Chiara (MBC - Torino) "Renal cells from spermatogonial germline stem cells protect against kidney injury" Letizia is working on a new project aimed to isolate human spermatogonial stem cells from testis biopsies. Concurrently to this, in the last few months she has started also a project on microvesicles (MVs) released by mesenchymal stem cells from human testis.
A paper from the group of Silvia Deaglio reports that NOTCH1 could be a potential target in CLL.
CLL is characterized by expansion of B lymphocytes, with a highly heterogeneous clinical behavior, thus requiring timely identification of high risk patients. NOTCH1 mutations are described in 5-10% newly diagnosed CLL, with frequency increasing in progressive/relapsed patients. NOTCH1 is a receptor that upon ligand binding undergoes successive cleavages, resulting in the release and nuclear translocation of the intra-cellular domain (NICD). Signaling is terminated by phosphorylation of the C-terminal PEST domain of NOTCH1, triggering its ubiquitination and degradation. Most mutations occur in exon 34 leading to PEST domain loss predicted to result in NOTCH1 impaired degradation, stabilization of NICD and deregulated signaling. In this paper, Francesca Arruga and colleagues studied NOTCH1 functional role in CLL patients with wild type (WT) or mutated (M) NOTCH1. M patients displayed accumulation of the active NICD and significantly higher levels of the main NOTCH1 target genes. Expression of NOTCH1 and of its targets varied across disease compartments, being higher in CLL cells from the lymph nodes (LN), as compared to paired cells from peripheral blood or bone marrow. Immunohistochemistry on LN samples, showed an intense nuclear staining in NOTCH1 M as opposed to the more cytoplasmic signal in WT, suggesting a more active NOTCH1 signaling.
Within LN biopsies from CLL patients, NOTCH1 ligand (Jagged1) was highly expressed on elements of myeloid origin. This finding prompted the in vitro recreation of a niche by co-culturing Jagged1+ nurse-like cells (NLC) with autologous CLL cells. Under these conditions, NOTCH1 activity in CLL cells was sustained, as shown by Q-PCR of target genes. Moreover, NLCs protect NOTCH1 M CLL cells from fludarabine-induced apoptosis. This effect was prevented pre-treating CLL cells with g-secretase inhibitors, to block NOTCH1 activation. These results show that PEST mutations have a stabilizing effect on NOTCH1 signaling. Micro-environmental interactions are critical in activating NOTCH1, creating local conditions that favour drug resistance, thus making NOTCH1 a potential target in CLL.
A paper from the group of Emanuela Tolosano in collaboration with the group of Franco Novelli demonstrated that the acute-Phase Protein Hemopexin Is a Negative Regulator of the Development of Experimental Autoimmune Encephalomyelitis, the mouse model of Multiple Sclerosis.
Multiple Sclerosis is a severe, chronic inflammatory disease of the central nervous system, due to the actvation of autoreactive CD4+ T cells. Hemopexin (Hx) is an acute-phase protein synthesized by hepatocytes in response to the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Hx is the plasma protein with the highest binding affinity to heme and controls heme-iron availability in tissues and also in T lymphocytes, where it modulates their responsiveness to IFN-γ. Recent data have questioned regarding an anti-inflammatory role of Hx, a role that may be both heme-binding dependent and independent. In this paper Rolla S. and Ingoglia G. et al. investigated the role of Hx in the development of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. After EAE induction, Hx content in serum increased and remained high during disease progression. When EAE was induced in Hx knockout (Hx-/-) mice, they developed a clinically earlier and exacerbated EAE compared with wild-type mice, associated to a higher amount of CD4+-infiltrating T cells. The severe EAE developed by Hx-/- mice could be ascribed to an enhanced expansion of Th17 cells accounting for both a higher disposition of naive T cells to differentiate toward the Th17 lineage and a higher production of Th17 differentiating cytokines IL-6 and IL-23 by APCs. When purified human Hx was injected in Hx-/- mice before EAE induction, Th17 expansion, as well as disease severity, were comparable with those of wild-type mice.
These data indicate that Hx has a negative regulatory role in Th17-mediated inflammation and prospect its pharmacological use to limit the expansion of this cell subset in inflammatory and autoimmune disease.
A paper from the group of Fiorella Altruda reports a novel regulator of pluripotency in mouse embryonic stem cells.
Pluripotency is a unique state in which cells can self-renew indefinitely whilst maintaining the ability to differentiate into multiple cell types of the body. Apart from the well studied core factors that transcriptionally regulate this process, several lines of evidence underscore the importance of RNA-based post-transcriptional regulation of gene expression in pluripotency maintenance. In this paper, Fagoonee et al. identify the RNA-binding protein ESRP1 (Epithelial splicing regulatory protein 1) as a candidate regulator of self renewal and pluripotency in ES cells on the basis of its conserved co-expression with well-established pluripotency factors. Depletion of ESRP1 in mouse ES cells results in increased self-renewal and impaired early differentiation in vitro. Moreover, ESRP1 binds to the mRNA of several pluripotency-related genes and decreases their polysomal loading, hence contributing to finely tune their expression levels in ES cells. Interestingly, downregulation of ESRP1 favors reprogramming of differentiated fibroblasts into pluripotent cells. The expression of ESRP1 in other stem cells, of both mouse and human origin, pinpoints the importance of this RNA-binding protein in stem cell biology. As ESRP1 is also involved in epithelial to mesenchymal transition, this study opens up new perspectives in the field of epithelial cancers and stem cells.