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We have shown that cyclic activation of the Wnt/b-catenin signalling pathway enhances cell-fusion-mediated reprogramming of a variety of somatic cells (Lluis et al., Cell Stem Cell 2008, Marucci et al. Cell Reports 2014). Tcf3 and Tcf1 are two key effectors in the pathway, and are essential in this process (Lluis et al., PNAS 2011; Ombrato et al., Cell Cycle 2012; Aulicino et al., Stem Cell Report 2014).

Currently we are studying how the dynamics of the Wnt pathway maintains cell pluripotency, and we are reconstructing the regulatory network that is controlled by b-catenin/Tcf factors that have pivotal roles in the regulation of pluripotency in embryonic stem cells and somatic cell reprogramming.

Using super-resolution fluorescence microscopy (stochastic optical reconstruction microscopy; STORM) (Rust et al., Nature Methods, 2006) in collaboration with the group of Melike Lakadamyali (Institute of Photonic Sciences, Barcelona) we have dissected out the nanoscale organization of nucleosome assembly, with high molecular specificity and spatial resolution in a variety of somatic and stem/ reprogrammed cells. We discovered that nucleosomes are arranged into discrete groups, which we called ‘nucleosome clutches’ (as an analogy with egg clutches). While somatic cells have dense and compacted clutches that contain tens of nucleosomes, clutches in pluripotent cells contain fewer and less compacted nucleosomes. Our findings have delineated a novel model of chromatin fiber assembly, and the relationship among the decoded structure and naïve pluripotency (Ricci et al. Cell 2015).

We are currently studying the changes in chromatin structure and organisation during somatic cell reprogramming and differentiation, to determine how chromatin fibers can be rearranged to overcome epigenetic barriers to gain pluripotency.

We have shown that upon activation of Wnt/b-catenin signalling, mouse retinal neurons can be transiently reprogrammed in vivo. These cells return to a precursor stage following their spontaneous fusion with transplanted haematopoietic stem and progenitor cells in damaged retinas. The newly formed hybrid cells reactivate neuronal precursor genes, and can thereby proliferate. The hybrids differentiate into neurons, which regenerate the damaged retinal tissue to provide functional rescue. Our data suggest that in-vivo reprogramming of terminally differentiated retinal neurons is a mechanism of tissue regeneration (Sanges et al., Cell Reports 2013).

We recently described retinal regeneration in rd10 mice, which is a model of retinitis pigmentosa, a severe disease that affects a large number of individuals and that results in progressive loss of vision (Sanges et al JCI 2010). Furthermore, we demonstrated cell-fusion mediated reprogramming as an efficient therapy for Parkinson’s disease, and as mechanism to control liver regeneration, an organ with high regenerative capacity in mammals (Altarche-Xifro et al eBiomedicine 2016; Pedone et al. Cell Reports 2017). We are also investigating the mechanisms controlling cell-to-cell fusion, and how ploidy is controlled in reprogrammed hybrids.

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