We 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). 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.). 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). More 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).

Using super-resolution fluorescence microscopy (stochastic optical reconstruction microscopy; STORM) in collaboration with Lakadamyali lab (UPENN), we identified a novel model of chromatin fibre organization and decoded the relation between this structure and naïve pluripotency (Ricci et al. Cell 2015; Otterstrom et al. NAR 2019). 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 discovered that RNA polymerase II-mediated supercoiling controls loop extrusion (Neguembor et al. Mol Cell 2021). Finally, more recently, we studied the relation between nascent RNA and the nucleosomes in the chromatin, and moreover, by combining super-resolution imaging and genomic approaches we derived models of genes at nucleosome level resolution (Castells-Garcia et al. NAR 2022; Neguembor et al. Nat. Struct. Mol. Biol. 2022).

We studied mechanisms of cell-to-cell fusion (Sottile et al. Cell Reports 2017) and ploidy maintenance (Frade et al. Science Advances 2019). Recently we discovered that human Muller Glia can fuse with different human cells and studied the differentiation of the hybrids (Bonilla-Pons et al eBioedicine 2022). In vivo, we previously 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 retinas and in turn we defined the chemokine-receptor interactions to enhance the migration and integration of transplanted cells into the mouse retina (Pesaresi et al. Molecular Therapy, 2021).