Research

Research Areas

Our research is directed at how cell death features (type, timing, extent) govern the type of regenerative strategy employed by a biological system.

We primarily use as model system the murine pancreas due to the wide-range of genetic tools available for this organ and its demonstrated cell plasticity potential. Besides employing classical systems of rapid cell-ablation (RIP-DTR, chemical ablation), we developed novel transgenic models of progressive β-cell decay (financed by Excellence

Map of pancreas plasticity (after Cigliola et al., 2016)

Project for Young Investigators of Novo Nordisk Foundation). By coupling the diverse β-cell ablation configurations with genetic cell tracing, timed conditional gene expression and diverse omics assays, we study the dynamical molecular fingerprint of β-cell death and the regenerative response employed, with focus on β-cell self-renewal potential (financed by FRIPRO Young Research Talent grant – Research Council of Norway). Moreover, we address the role of senescence-based cell-plasticity breaks on β-cell regeneration potential and modulate the age-related switch leading to β-cell quiescence by using genetic and pharmacological tools (financed by Excellence Project for Young Investigators of Novo Nordisk Foundation). Currently, we plan to activate the compensatory cell proliferation response in the β-cell compartment either by conditional gene expression or by releasing the proliferative instructive signals from β-cells trapped in a perpetual “undead” state.

Besides the in vivo approach, we also employ differentiating patient-specific induced pluripotent stem cells (iPSC) and organoids for disease modeling. We coupled these systems with large-scale imaging and omics in order to study β-cell fate acquisition, decay and proliferation (financed by STAMCELLER “STEMCELLS” Young Research Talent grant – Research Council of Norway). We recently characterized the positive impact of cell confinement on promoting the human iPSC differentiation potential towards the different pancreatic islet cell signatures, via an integrin-based mechanism (Legøy et al, 2020 Sci. Rep.). Currently we further investigate the influence of mechanical forces and adhesion on cell differentiation by using thermo-responsive hydrogels allowing the incremental alteration of their rigidity and density (financed by NCMM seeding grant).

A. HNF1A and HNF4A are induced in vivo (from Legøy et al.,[Chera], Front Cell Dev Biol, 2020); B. hyperglycemia perturbs islet identity confinement (from Legøy et al.,[Chera] Acta Physiol, 2020).

Recently, by using xenotransplanted differentiating pancreatic progenitors derived from human induced pluripotent stem cells (hiPSC), my laboratory uncovered an essential role of HNF1A and HNF4A induction for restricting and maintaining islet cell identity in vivo (Legøy et al., 2020 Front. Cell Dev Biol). Briefly, the modelling of the proteome landscape characterizing the in vivo differentiating cells showed that the two factors were leading regulators of the islet promoting in vivo effect. Their induction was associated to an active inhibition of α-cell identity in β-cells, apparently through the regulation of specific epigenetic regulators maintaining the key α-cell fate determinant (Arx) silenced. This cell identity confinement is disrupted by hyperglycemia-caused changes in the redox balance, resulting in the accumulation of cells with mixed α/β identity with a landscape profile typical of HNF4A activation (Legøy et al.,2020 Acta Physiol.).

Schematic representation of the in vivo HNF1A / HNF4A balance tilt effects in humans (after Legøy et al.,[Chera] Front. Cell Dev. Biol. 2020).

As a distinct model of homeostasis disruption, we study the dysfunction of evolutionarily conserved cell plasticity breaks and the subsequent cell identity loss in the initiation of tumour development. Along these lines, we recently performed a pilot global proteome study on patients diagnosed with Non-Muscle Invasive Bladder cancer (NMIBC). Unexpectedly, we also identified molecular cancer signatures in several of the apparently healthy biopsies (Berle, et al.[Chera], PLoS One, 2018). These patients relapsed faster, presenting a far more aggressive form of bladder cancer. The outlier samples as well as the tumour biopsies displayed the deregulation of several signalling pathways involved in cell identity maintenance, indicating that analysing apparently healthy tissue of a cancer-invaded organ may suggest disease progression.

By using these approaches our main research goal is to identify core mechanisms governing the crosstalk between cell death and self-renewal regenerative strategies in response to diverse homeostasis disruption.

FUNDING

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Want to join the lab? Master and PhD student candidates interested in cell fate decisions, islet cell plasticity and molecular networks are encouraged to contact Simona Chera (simona.chera [at] uib.no).