The Cosma lab discovered that activation of the Wnt/beta-catenin signalling pathway enhances cell-fusion-mediated reprogramming of a variety of somatic cells (Lluis et al., Cell Stem Cell 2008, Stem Cells 2010). Furthermore, the lab proposed that Tcf3 functions as a repressor of the reprogramming potential of somatic cells by largely modulating epigenome modifications during the reprogramming process (Lluis et al., PNAS 2011; Ombrato et al., Cell Cycle 2012). Further key observations showed that fluctuations of the Wnt signalling pathway control the maintenance of mESC pluripotency and are essential for reprogramming (Marucci et al. Cell Reports 2014; Aulicino et al. Stem Cell Reports 2014; Aulicino et al. Stem Cell Reports 2020). The lab also showed that Wnt activity regulates cell cycle in mESCs and safeguards mESCs epigenetic stability (De Jaime-Soguero et al, Plos Genetics 2017; Theka et al. Scientific Reports 2019). Recently In collaboration with Andrea Califano (Columbia University, USA) we used reverse engineering algorithms to identify “Master Regulators” (MRs) of reprogramming and pluripotency. We identified BAZ2B as an MR able to convert human hematopoietic progenitors into hematopoietic stem cells enhancing their long-term clonogenicity and stemness after transplantation (Arumugam et al. Cell Reports, 2020).
Decoding chromatin and DNA structure in cells undergoing reprogramming and differentiation, using super-resolution microscopy.
Using super-resolution fluorescence microscopy (stochastic optical reconstruction microscopy; STORM) in collaboration with Lakadamyali lab (UPENN, USA) we identified a novel model of chromatin fibre organization and decoded the relation between this structure and naïve pluripotency (Ricci et al. Cell 2015). Furthermore, we set up a novel approach to image non-repetitive genomic regions with nanoscale resolution and in living cells (Neguembor et al. NAR 2018). We also visualize how histone tail acetylation impacts DNA compaction at nanoscale level and identified the clutch DNA lying within a specific nanoscale zone from the center of the nucleosome clutch (Otterstrom et al, NAR 2019). Finally, using single molecule tracking (SMT) we showed that nucleosomes are dynamic and their local mobility within chromatin relates to the structural features observed in super-resolution images and mesoscale models (Gomez-Garcia et al. Cell Reports, in press). Using super resolution microscopy, we are interested in studying the 3D genome organization (Cosma & Lakadamyali Nature Methods 2020) and we are currently investigating mechanism of chromatin loop formation.
We studied mechanisms of cell-to-cell fusion (Sottile et al. Cell Reports 2017) and ploidy maintenance (Frade et al. Science Advances 2019). We showed that bone marrow (BM) cells fuse with retinal neurons and Muller glia cells in degenerated mouse retinas. The in-vivo formed hybrids undergo reprogramming and regenerate neurons in drug-induced and genetic models of retinal degeneration (Sanges et al. Cell Reports 2013; J. of Clinical Investigation 2016; Pesaresi et al. eBiomedicine 2018). Furthermore, other key discoveries showed that BM-derived hybrids can functionally rescue dopaminergic neurons in two Parkinson’s disease mouse models (Altarche-Xifro et al., eBiomedicine 2016) and regenerate mouse liver after hepatectomy (Pedone et al., Cell Reports 2017). Finally, we recently identified the released chemokines from damaged human and mouse retina and in turn we defined the chemokine-receptor interactions to enhance migration and integration of transplanted cells into the mouse retina (Pesaresi et al. Molecular Therapy, 2020).