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Byung Ho Lee#, Kana Fuji, Heike Petzold, Philip Allan Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton#
Permeability-driven pressure and cell proliferation control lumen morphogenesis in pancreatic organoids.
Nat Cell Biol, Art. No. doi: 10.1038/s41556-025-01832-5 (2025)
Open Access PubMed Source   

Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment.
@article{Lee9103,
author={Byung Ho Lee, Kana Fuji, Heike Petzold, Philip Allan Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton},
title={Permeability-driven pressure and cell proliferation control lumen morphogenesis in pancreatic organoids.},
journal ={Nature cell biology},
volume={},
pages={1--1},
year=2025
}

Aswin Vinod Muthachikavil, Alexander von Appen, Thomas D Kühne
Computational Characterization of the Role of LEM2/LaminA Interactions on the Stability of BAF-Dimer Using Molecular Simulations.
Proteins, Art. No. doi: 10.1002/prot.70105 (2025)
Open Access PubMed Source   

The effect of the presence of the BAF-binding LEM-domain and LaminA Ig-fold on the stability of the BAF dimer was studied qualitatively using non-equilibrium pull simulations and quantitatively through the calculation of the potential of mean force profile along BAF-BAF separation distance. We find that hydrophobicity plays a significant role in stabilizing the BAF dimer when LEM-domain and LaminA are bound. The role of LEM-domain and LaminA in stabilizing the BAF dimer is explored by quantifying the strength of interaction between them, which are critical components of the nuclear lamina.
@article{Muthachikavil9104,
author={Aswin Vinod Muthachikavil, Alexander von Appen, Thomas D Kühne},
title={Computational Characterization of the Role of LEM2/LaminA Interactions on the Stability of BAF-Dimer Using Molecular Simulations.},
journal ={Proteins},
volume={},
pages={1--1},
year=2025
}

Lei Yuan*, Sagarika Dawka*, Yohan Kim*, Anke Liebert*, Fabian Rost, Robert Arnes-Benito, Franziska Baenke, Christina Götz, David Long Hin Tsang, Andrea Schuhmann, Anna Shevchenko, Roberta Rezende de Castro, Seunghee Kim, Aleksandra Sljukic, Anna Dowbaj, Andrej Shevchenko, Daniel Seehofer, Dongho Choi, Georg Damm, Daniel E Stange, Meritxell Huch
Human assembloids recapitulate periportal liver tissue in vitro.
Nature, Art. No. doi: 10.1038/s41586-025-09884-1 (2025)
Open Access PubMed Source   

The development of complex multicellular human in vitro systems holds great promise for modelling disease and advancing drug discovery and tissue engineering1. In the liver, despite the identification of key signalling pathways involved in hepatic regeneration2,3, in vitro expansion of human hepatocytes directly from fresh patient tissue has not yet been achieved, limiting the possibility of modelling liver composite structures in vitro. Here we first developed human hepatocyte organoids (h-HepOrgs) from 28 different patients. Patient-derived hepatocyte organoids sustained long-term expansion of hepatocytes in vitro and maintained patient-specific gene expression and bile canaliculus features and function of the in vivo tissue. After transplantation, expanded h-HepOrgs rescued the phenotype of a mouse model of liver disease. By combining h-HepOrgs with portal mesenchyme and our previously published cholangiocyte organoids4-6, we generated patient-specific periportal liver assembloids that retain the histological arrangement, gene expression and cell interactions of periportal liver tissue, with cholangiocytes and mesenchyme embedded in the hepatocyte parenchyma. We leveraged this platform to model aspects of biliary fibrosis. Our human periportal liver assembloid system represents a novel in vitro platform to investigate human liver pathophysiology, accelerate drug development, enable early diagnosis and advance personalized medicine.
@article{Yuan9100,
author={Lei Yuan, Sagarika Dawka, Yohan Kim, Anke Liebert, Fabian Rost, Robert Arnes-Benito, Franziska Baenke, Christina Götz, David Long Hin Tsang, Andrea Schuhmann, Anna Shevchenko, Roberta Rezende de Castro, Seunghee Kim, Aleksandra Sljukic, Anna Dowbaj, Andrej Shevchenko, Daniel Seehofer, Dongho Choi, Georg Damm, Daniel E Stange, Meritxell Huch},
title={Human assembloids recapitulate periportal liver tissue in vitro.},
journal ={Nature},
volume={},
pages={1--1},
year=2025
}

Kexin Wang, Aida Maraj, Anna Seigal
Contrastive independent component analysis for salient patterns and dimensionality reduction.
Proc Natl Acad Sci U.S.A., 122(50) Art. No. e2425119122 (2025)
Open Access PubMed Source   

In recent years, there has been growing interest in jointly analyzing a foreground dataset, representing an experimental group, and a background dataset, representing a control group. The goal of such contrastive investigations is to identify salient features in the experimental group relative to the control. Independent component analysis (ICA) is a powerful tool for learning independent patterns in a dataset. We generalize it to contrastive ICA (cICA). For this purpose, we devise a linear algebra-based tensor decomposition algorithm, which is more expressive but just as efficient and identifiable as other linear algebra-based algorithms. We establish the identifiability of cICA and demonstrate its performance in finding patterns and visualizing data, using synthetic, semisynthetic, and real-world datasets, comparing the approach to existing methods.
@article{Wang9099,
author={Kexin Wang, Aida Maraj, Anna Seigal},
title={Contrastive independent component analysis for salient patterns and dimensionality reduction.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={122},
issue ={50},
pages={1--1},
year=2025
}

Oscar Wing Ho Chua, Linghan Duan, Svenja H Bothe, Valentin Evsyukov, Claudia Moebius, Marc Bickle, Günter U Höglinger#, Matthias Höllerhage#
Inhibition of TGF-beta signaling protects from alpha-synuclein induced toxicity.
Cell Death Discov, Art. No. doi: 10.1038/s41420-025-02901-2 (2025)
Open Access PubMed Source   

Parkinson's disease (PD) is histopathologically defined by the presence of Lewy bodies, which are intracellular proteinaceous inclusions that contain mainly aggregated alpha-synuclein (aSyn). It is believed that oligomeric intermediates between monomeric aSyn and large aggregates are neurotoxic, which would lead to the demise of dopaminergic neurons. Therefore, novel therapies preventing aSyn-induced cell death need to be developed. Therefore, we performed a genome-wide siRNA screening in an aSyn-induced dopaminergic cell death model and found the knockdown of three transforming growth factor-beta (TGFb) pathway-related genes to be protective. Hence, we hypothesized that a reduction in TGFb signaling would protect dopaminergic neurons from aSyn-induced toxicity. Thus, we validated the results of the genome-wide knockdown screening with the use of two different types of siRNAs. We confirmed that the knockdown of Activin receptor-like kinase 5 (ALK5) and Mothers against decapentaplegic homolog 2 (SMAD2), two genes of the TGFb pathway, protected dopaminergic neurons from aSyn-induced toxicity. An increase in TGFb signaling by treatment with TGFb ligands further exacerbated aSyn-induced toxicity, whereas this effect was mitigated by knockdown of ALK5, SMAD2, or Dynein light chain roadblock type-1 (DYNLRB1). Moreover, TGFb ligand treatment induced an up-regulation of SNCA mRNA expression in aSyn-overexpressing cells. Interestingly, consistent with the literature, we identified an up-regulation of the genes of the TGFb pathway in aSyn-overexpressing cells. Altogether, we identified a potential protective role by interference with the TGFb pathway against aSyn-induced toxicity. These findings provide a rationale for the development of novel strategies against PD.
@article{Chua9097,
author={Oscar Wing Ho Chua, Linghan Duan, Svenja H Bothe, Valentin Evsyukov, Claudia Moebius, Marc Bickle, Günter U Höglinger, Matthias Höllerhage},
title={Inhibition of TGF-beta signaling protects from alpha-synuclein induced toxicity.},
journal ={Cell death discovery},
volume={},
pages={1--1},
year=2025
}

Indra Niehaus, Michaela Wilsch-Bräuninger, Felipe Mora-Bermúdez, Fabian Rost, Mihaela Bobic-Rasonja, Velena Radosevic, Marija Milkovic-Perisa, Pauline Wimberger, Mariasavina Severino, Alexandra Haase, Ulrich Martin, Karolina Kuenzel, Kaomei Guan, Katrin Neumann, Noreen Walker, Evelin Schröck, Natasa Jovanov-Milosevic, Wieland Huttner#, Nataliya Di Donato#, Michael Heide#
Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.
EMBO Rep, Art. No. doi: 10.1038/s44319-025-00647-7 (2025)
Open Access PubMed Source   

Actins are cytoskeletal proteins that are essential for multiple cellular processes. Mutations in the ACTB and ACTG1 genes, encoding the ubiquitous beta- and gamma-cytoskeletal actin isoforms, respectively, cause a broad spectrum of neurodevelopmental disorders, with microcephaly as the most frequent one. To investigate the pathogenesis underlying this cortical malformation, we studied patient-derived cerebral organoids from induced pluripotent stem cells of individuals with the Baraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) carrying an ACTB/ACTG1 missense mutation. These organoids were reduced in size, showing a thinner ventricular zone (VZ) due to reduced VZ progenitor abundance. Strikingly, VZ progenitors in BWCFF-S cerebral organoids displayed a shift in the orientation of their cleavage plane from a predominantly vertical to a majoritarian horizontal orientation. The latter cleavage plane orientation is incompatible with increasing VZ progenitor abundance and instead promotes basal progenitor generation. Various cytoskeletal and morphological irregularities of BWCFF-S VZ progenitors, notably in the apical region, seemingly contribute to this change in cleavage plane orientation. Our results provide insight into the cell biological basis of the microcephaly associated with BWCFF-S caused by actin mutations.
@article{Niehaus9098,
author={Indra Niehaus, Michaela Wilsch-Bräuninger, Felipe Mora-Bermúdez, Fabian Rost, Mihaela Bobic-Rasonja, Velena Radosevic, Marija Milkovic-Perisa, Pauline Wimberger, Mariasavina Severino, Alexandra Haase, Ulrich Martin, Karolina Kuenzel, Kaomei Guan, Katrin Neumann, Noreen Walker, Evelin Schröck, Natasa Jovanov-Milosevic, Wieland Huttner, Nataliya Di Donato, Michael Heide},
title={Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly.},
journal ={EMBO reports},
volume={},
pages={1--1},
year=2025
}

Anna Czarkwiani*, Macrina Lobo*, Lizbeth Airais Bolaños Castro*, Andreas Petzold, Fabian Rost, René Maehr#, Maximina H Yun#
Molecular basis for de novo thymus regeneration in a vertebrate, the axolotl.
Sci Immunol, 10(114) Art. No. 9903 (2025)
PubMed Source   

The thymus is the primary site of T cell development, central to the establishment of self-tolerance and adaptive immune function. In mammals, the thymus undergoes age-related involution, resulting in a global decline in immune function. The thymus has some regenerative ability that relies on pre-existing thymic remnants but is insufficient to prevent involution. Here, we show that the juvenile axolotl (Ambystoma mexicanum) is able to regenerate its thymus de novo after complete removal, constituting an exception among vertebrates. Using single-cell transcriptomics and genetic and transplantation approaches, we demonstrate that de novo thymus regeneration results in the restoration of morphology, cell-type diversity, and function. FOXN1, although it has a conserved role in thymus organogenesis, is dispensable for the initiation of thymic regeneration. In contrast, we identify midkine signaling as a possible early driver of de novo thymus regeneration. This study demonstrates an instance of organ-level regeneration of the lymphoid system, which could guide future clinical strategies seeking to promote thymus regrowth.
@article{Czarkwiani9096,
author={Anna Czarkwiani, Macrina Lobo, Lizbeth Airais Bolaños Castro, Andreas Petzold, Fabian Rost, René Maehr, Maximina H Yun},
title={Molecular basis for de novo thymus regeneration in a vertebrate, the axolotl.},
journal ={Science immunology},
volume={10},
issue ={114},
pages={null--null},
year=2025
}

Ruben I Calderon, Nirvay Sah, Molly Huang, Sampada Kallol, Ryan H Kittle, Walee B Shaik, Ahmed Abdelbaki, Jennifer N Chousal, Robert Morey, Tony Bui, Alejandra Mitre, Norah M E Fogarty, Claudia Gerri, Zoe Manalo, Claire Zheng, Peter De Hoff, Pratik Home, Kathy K Niakan, Heidi Cook-Andersen, Kathleen M Fisch, Soumen Paul, Francesca Soncin
VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment.
Proc Natl Acad Sci U.S.A., 122(48) Art. No. e2508432122 (2025)
Open Access PubMed Source   

The trophectoderm (TE), the first lineage specified during mammalian development, initiates implantation and gives rise to placental trophoblasts. While animal models have elucidated key conserved signaling pathways involved in early TE specification, including bone morphogenetic protein (BMP), WNT, and HIPPO, species-specific differences during early development emphasize the need for human-specific models. We previously identified VGLL1, a coactivator of TEAD transcription factors, as a human-specific placental marker. In this study, we employed a pluripotent stem cell (PSC)-based model of TE induction by BMP4 to investigate chromatin remodeling and transcriptional dynamics during TE formation. BMP4-induced chromatin accessibility changes promoted a trophoblast gene expression program, while mesoderm lineage markers were only transiently expressed upon canonical WNT activation. We found that VGLL1 was expressed downstream of key TE transcription factors (GATA2/3, TFAP2A/C) but was essential for establishment of full trophoblast identity by up-regulating the epidermal growth factor receptor (EGFR) and reinforcing GATA3 expression through positive feedback. Notably, VGLL1 enhanced canonical WNT signaling via direct regulation of WNT receptors and effectors. We also identified KDM6B, a histone demethylase that removes H3K27me3 repressive marks, as a direct VGLL1 target. KDM6B facilitated activation of bivalent promoters associated with TE markers, linking epigenetic regulation to lineage identity. Our findings establish a mechanistic framework positioning VGLL1 as a central regulator that integrates HIPPO, BMP, and WNT signaling pathways to drive establishment of human TE.
@article{Calderon9094,
author={Ruben I Calderon, Nirvay Sah, Molly Huang, Sampada Kallol, Ryan H Kittle, Walee B Shaik, Ahmed Abdelbaki, Jennifer N Chousal, Robert Morey, Tony Bui, Alejandra Mitre, Norah M E Fogarty, Claudia Gerri, Zoe Manalo, Claire Zheng, Peter De Hoff, Pratik Home, Kathy K Niakan, Heidi Cook-Andersen, Kathleen M Fisch, Soumen Paul, Francesca Soncin},
title={VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={122},
issue ={48},
pages={null--null},
year=2025
}

Taylor Brysiewicz#, Aida Maraj#
Lawrence lifts, matroids, and maximum likelihood degrees.
Algebr Stat, 16(2) 217-242 (2025)
Source   

We express the maximum likelihood (ML) degrees of a family of toric varieties in terms of Möbius invariants of matroids. The family of interest are those parametrized by monomial maps given by Lawrence lifts of totally unimodular matrices with even circuits. Specifying these matrices to be vertex-edge incidence matrices of bipartite graphs gives the ML degrees of some hierarchical models and three dimensional quasi-independence models. Included in this list are the no-three-way interaction models with one binary random variable, for which we give closed formulae.
@article{Brysiewicz9102,
author={Taylor Brysiewicz, Aida Maraj},
title={Lawrence lifts, matroids, and maximum likelihood degrees.},
journal ={Algebraic Statistics},
volume={16},
issue ={2},
pages={217--242},
year=2025
}

Anna Hadarovich, Maxim Scheremetjew, Hari Raj Singh, HongKee Moon, Lena Hersemann, Agnes Toth-Petroczy
PICNIC web server for predicting proteins involved in biomolecular condensates.
Bioinformatics, Art. No. doi: 10.1093/bioinformatics/btaf647 (2025)
Open Access PubMed Source   

Biomolecular condensates have been implicated in key cellular processes such as gene regulation, stress response, and signaling, and dysregulation of condensates has been linked to neurodegeneration and other diseases. Computational algorithms that predict protein condensation can aid systematic characterization of biomolecular condensates at the proteome scale. However, many experimental labs may lack the computational background or resources to run sophisticated prediction tools locally.
@article{Hadarovich9095,
author={Anna Hadarovich, Maxim Scheremetjew, Hari Raj Singh, HongKee Moon, Lena Hersemann, Agnes Toth-Petroczy},
title={PICNIC web server for predicting proteins involved in biomolecular condensates.},
journal ={Bioinformatics (Oxford, England)},
volume={},
pages={1--1},
year=2025
}
* joint first authors, # joint corresponding authors