Biology subjects

Scheibner, K.

Publications and source records attributed to Scheibner, K..

3 recordsLinked to original sources

bioRxiv2025

Endocrine-enriched stem cell-derived islets improve long-term safety in vivo

Fully differentiated stem cell-derived islets (SC-islets) are proven to normalise blood glucose in type 1 diabetic patients. However, the presence of off-target cell types and the immature SC-islet function upon transplantation remain unresolved problems. Here, we established sorting strategies to generate SC-islets with defined glucagon-producing SC-- and insulin-producing {beta}-cell ratios and assessed their safety and efficacy in vitro and in vivo. Engineering SC-islets is beneficial to the insulin response in vitro, which does not translate to improved glycaemic regulation in vivo. Importantly, hormone-producing endocrine cell enrichment and thus off-target cell type depletion eliminated the risk for unwanted outgrowth in vivo. Single cell analysis defined off-target cells in vitro and in vivo and identified marker genes to assess SC-islet quality and define safety release criteria before graft transplantation. This study highlights the importance of determining the SC-islet composition and establishing rigorous quality controls to ensure long-term safety for {beta}-cell replacement therapy.

bioengineering↗

bioRxiv2021

Synaptotagmin 13 orchestrates pancreatic endocrine cell egression and islet morphogenesis

Epithelial cell egression is important for organ development, but also drives cancer metastasis. Better understandings of pancreatic epithelial morphogenetic programs generating islets of Langerhans aid to diabetes therapy. Here we identify the Ca2+-independent atypical Synaptotagmin 13 (Syt13) as a key driver of endocrine cell egression and islet formation. We detected upregulation of Syt13 in endocrine precursors that correlates with increased expression of unique cytoskeletal components. High-resolution imaging reveals a previously unidentified apical-basal to front-rear repolarization during endocrine cell egression. Strikingly, Syt13 interacts with acetylated tubulin and phosphatidylinositol phospholipids and localizes to the leading-edge of egressing cells. Knockout of Syt13 impairs endocrine cell egression and skews the - to-{beta}-cell ratio. Mechanistically, Syt13 regulates endocytosis to remodel the basement membrane and cell-matrix adhesion at the leading-edge of egressing endocrine cells. Altogether, these findings implicate an unexpected role of Syt13 in regulating cell polarity to orchestrate endocrine cell egression and islet morphogenesis.

developmental biology↗

bioRxiv2019

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2.

Pioneer transcription factors (PTF) can recognize their binding sites on nucleosomal DNA and trigger chromatin opening for recruitment of other non-pioneer transcription factors. However, critical properties of PTFs are still poorly understood, such as how these transcription factors selectively recognize cell type-specific binding sites and under which conditions can they can initiate chromatin remodelling. Here we show that early endoderm binding sites of the paradigm PTF Foxa2 are epigenetically primed by low levels of active chromatin modifications in embryonic stem cells (ESC). Priming of these binding sites is supported by preferential recruitment of Foxa2 to endoderm binding sites compared to lineage-inappropriate binding sites, when ectopically expressed in ESCs. We further show that binding of Foxa2 is required for chromatin opening during endoderm differentiation. However, increased chromatin accessibility was only detected on binding sites which are synergistically bound with other endoderm transcription factors. Thus, our data suggest that binding site selection of PTFs is directed by the chromatin environment and that chromatin opening requires collaboration of PTFs with additional transcription factors.

genomics↗