Biology subjects

Herr, C.

Publications and source records attributed to Herr, C..

6 recordsLinked to original sources

bioRxiv2025

Nanotopographic Control of Actin Waves and Growth Cone Navigation in Developing Neurons

The development of axons and dendrites (neurites) in a neural circuit relies on the dynamic interplay of cytoskeletal components, especially actin, and the integration of diverse environmental cues. Building on prior findings that actin dynamics can serve as a primary sensor of physical guidance cues, this work investigates the role of nanotopography in modulating and guiding actin waves and neurite-tip dynamics during early neural circuit development. Although actin dynamics is well known to contribute to pathfinding in wide axonal tips, typically referred to as growth cones, we also observe dynamic actin remodeling throughout neurites and at other, narrower, neurite tips. We find that actin-wave speeds do not change significantly in the first two weeks of neurite development on flat substrates, but decrease over the same period in neurites on nanoridges. The ability of nanoridges to guide actin waves and the neurite-tip direction also decreases as neurites mature, both for narrow tips and wide growth cones. This change in responsiveness to physical guidance cues with neuronal maturation may impact the regenerative capacity of developing neural cells that are inserted into mature brains.

biophysics↗

bioRxiv2025

Estradiol alters actin and protrusion dynamics in endometriotic epithelial cells

Estradiol (E2), a sex steroid hormone molecule, plays a key role in regulating the actin and shape dynamics of cells in a multitude of normal and pathophysiological conditions. While cytoskeletal rearrangements, membrane dynamics, and cellular protrusions are intimately involved in cell motility and invasiveness, little is known about the impact of E2 on these processes in estrogen-dependent epithelial cells. In this study, we quantified the impact of E2 on cell shape and actin dynamics in 12Z human endometriotic epithelial cells transfected with LifeAct-GFP and observed with lattice lightsheet microscopy, a new imaging technique fast enough to capture 3D dynamics on second timescales. E2, when applied for 24 hours, significantly decreased cell circularity, solidity, and rate of change of circularity, indicating a transition to a more elongated and less variable morphology. 24-hour E2 treatment also induced the formation of large membrane protrusions reminiscent of invadopodia and led to a more disordered flow of actin within those protrusions. However, these effects were not seen after 15 minutes of E2 treatment, suggesting that longer-term signaling is required to drive these structural changes. Together, these results suggest that E2 modulates actin polymerization and membrane protrusion dynamics in endometriotic epithelial cells and may prime them for cell invasion. This work highlights a role for hormonal signaling in mediating cytoskeletal plasticity and migratory cell phenotypes.

biophysics↗

bioRxiv2023

Modeling of lung-liver interaction during infection in a human microfluidic organ-on-a-chip

BackgroundInfections of the respiratory tract such as pneumonia or COVID-19 cause high mortality and morbidity worldwide. Organ-on-a-chip (OC) technologies have been developed in the last years to establish human-based disease models, to study basic disease mechanisms and to provide a tool to speed up drug development. The aim of this study was to establish a lung-liver microfluidic system to study the interaction of both organ modules during infection. MethodsA two organ (lung / liver) microfluidic system was established using primary human bronchial (HBECs) or alveolar type epithelial cells (ATC) for the lung module and Huh-7 cells for the liver module. Inactivated non typeable Haemophilus influenzae (NTHi) and Pseudomonas aeruginosa PAO1 (PAO1) were applied to the lung module. Secreted mediators were screened by dot-blot analysis and quantified. The effect of lung epithelial bacterial stimulation on the liver cell transcriptome was analyzed by mRNA sequencing. ResultsLung and liver cells established stable cultures in a circulatory microfluidic system. Activation of HBECs or ATCs with NTHi or PAO1 resulted in the secretion of multiple inflammatory mediators into the microfluidic medium including TNF-, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-3 (MIP-3). Addition of lung cells and application of bacterial onto the HBECs module resulted in the gross change of the transcriptome of the liver cell module. Gene ontology enrichment analysis showed the induction of various pathways involved in host defense, metabolisms, repair, and acute phase response. InterpretationIn conclusion, a two-organ lung/liver microfluidic system was established to study the interaction of the organ modules during infection. Mediators released from epithelial culture modules into the microfluidic circulation after exposure to bacterial pathogens significantly modify the gene expression patterns of liver cells. FundingThis research was funded by the German Federal Ministry of Education and Research (BMBF), 031L0153 VISION "Alternativmethoden zum Tierversuch" and the Dr. Rolf M. Schwiete Stiftung.

cell biology↗

bioRxiv2023

Mutual regulation of transcriptomes between pneumocytes and fibroblasts mediates alveolar regeneration

Alveolar type 2 (AT2) and club cells are part of the stem cell niche of the lung and their differentiation is required for pulmonary homeostasis and tissue regeneration. A disturbed crosstalk between fibroblasts and epithelial cells contributes to the loss of lung structure in chronic lung diseases. Therefore, it is important to understand how fibroblasts and lung epithelial cells interact during regeneration. Here we analyzed the interaction of fibroblasts and the alveolar epithelium modelled in air-liquid interface cultures. Single-cell transcriptomics showed that co-cultivation with fibroblasts leads to increased expression of type 2 markers in pneumocytes, activation of regulons associated with maintenance of alveolar type 2 cells, and trans-differentiation of club cells towards pneumocytes. This was accompanied by an intensified transepithelial barrier. Vice versa, activation of NF{kappa}B pathways and the CEBPB regulon as well as the expression of IL-6 and other differentiation factors (e.g. FGFs) were increased in fibroblasts co-cultured with epithelial cells. Recombinant IL-6 enhanced epithelial barrier formation. Therefore, in our co-culture model, regulatory loops were identified by which lung epithelial cells mediate regeneration and differentiation of the alveolar epithelium in a cooperative manner with the mesenchymal compartment.

cell biology↗

bioRxiv2021

Spontaneous polarization and cell guidance on asymmetric nanotopography

Asymmetric nanotopography with sub-cellular dimensions has recently been demonstrated to be able to provide a unidirectional bias in the migration of cells. The details of this guidance depend both on the type of cell studied and the design of the nanotopography. This behavior is not yet well understood, so there is a pressing need for a predictive description of cell migration on such nanotopography that captures both the initiation of migration and the manner in which cell migration evolves. Here, we employ a three-dimensional, physics-based model to study cell guidance on asymmetric nanosawteeth. In agreement with experimental data, our model predicts that asymmetric sawteeth lead both to spontaneous motion and changes in motion phenotypes. Our model demonstrates that asymmetric nano-sawteeth induce a unidirectional bias in guidance direction that is dependent upon the actin polymerization rate and the sawtooth dimensions. Motivated by this model, an analysis of previously reported experimental data indicates that the degree of guidance by asymmetric nanosawteeth increases with the cell velocity.

biophysics↗

bioRxiv2021

Autoantibodies against Progranulin and IL-1 receptor antagonist in critically ill COVID-19

STRUCTURED ABSTRACTHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, associated with autoantibodies in a proportion of patients, lead to severe courses of disease. In addition, hyperactive responses of the humoral immune system have been described. In the current study we investigated a possible role of neutralizing autoantibodies against antiinflammatory mediators. Plasma from adult patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-1-Ra, IL-10, IL-18BP, IL-22BP, IL-36-Ra, CD40, IFN-2, IFN-{gamma}, IFN-{omega} and serpinB1. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. In a discovery cohort with severe to critical COVID-19 high titers of PGRN-autoantibodies were detected in 11 of 30 (36.7%), and of IL-1-Ra-autoantibodies in 14 of 30 (46.7%) patients. In a validation cohort of 64 patients with critical COVID-19 high-titer PGRN-Abs were detected in 25 (39%) and IL-1-Ra-Abs in 32 of 64 patients (50%). PGRN-Abs and IL-1-Ra-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-Ra-Abs were detected in low frequency (i.e. in < 5% of patients) and at low titers. Neither PGRN-nor IL-1-Ra-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2 or 188 unvaccinated healthy controls. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins nor against IL-1-Ra. Plasma levels of both free PGRN and free IL-1-Ra were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID-19 controls. In vitro PGRN-Abs from patients functionally reduced PGRN-dependent inhibition of TNF- signaling, and IL-1-Ra-Abs from patients reduced IL-1-Ra- or anakinra-dependent inhibition of IL-1{beta} signaling. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a hyperphosphorylated IL-1-Ra isoform was only found in patients with high-titer IL-1-Ra-Abs. Thr111 was identified as the hyperphophorylated amino acid of IL-1-Ra. In longitudinally collected samples hyperphosphorylated isoforms of both PGRN and IL-1-Ra emerged transiently, and preceded the appearance of autoantibodies. In hospitalized patients, the presence of IL-1-Ra-Abs or IL-1-Ra-Abs in combination with PGRN-Abs was associated with a higher morbidity and mortality. To conclude, neutralizing autoantibodies to IL-1-Ra and PGRN occur in a significant portion of patients with critical COVID-19, with a concomitant decrease in circulating free PGRN and IL-1-Ra, indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical hyperphosphorylated isoforms of both antigens, whose appearances precede autoantibody induction. Our data suggest that these immunogenic secondary modifications are induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection and predispose for a critical course of COVID-19.

immunology↗