Biology subjects

Maurer, M.

Publications and source records attributed to Maurer, M..

11 recordsLinked to original sources

bioRxiv2026

Pathways regulating the excitability of sympathetic neurons derived from human induced pluripotent stem cells

Postganglionic sympathetic neurons not only regulate target organs but also their own intrinsic activity and can be further modulated by parasympathetic neurons. This crosstalk and automodulatory signalling have been implicated in cardiovascular disorders, with the majority of earlier work employing rodent models. Here, we have used human sympathetic neurons derived from induced pluripotent stem cells (hiPSCs), as a scalable human in vitro system with the aim to investigate these pathways. Efficient differentiation of hiPSCs into sympathetic neurons was confirmed using molecular characterisation for the expression of PHOX2B, DBH, TH, PRPH. We employed Ca2+ imaging and whole-cell patch-clamp electrophysiology, to examine the neuronal functional properties and found that hiPSC-derived sympathetic neurons recapitulate key physiological features of the rodent native counterparts. Most cells responded to nicotine and expressed functional 2 adrenergic and muscarinic receptors, involved in sympathetic autoregulation and parasympathetic crosstalk. We further demonstrated that 2 adrenergic and muscarinic receptors inhibit membrane excitability (increased rheobase, hyperpolarisation, reduced input resistance) and that both types of receptors converge on inwardly rectifying K+ channels (GIRK) as effectors. The GIRK blocker Tertiapin-Q significantly reduced the 2 adrenergic and muscarinic responses, while the activator ML297 mimicked their action. Analysis of mouse stellate scRNA-seq confirmed that the receptors and GIRK subtypes studied here are prominently expressed in native sympathetic neurons. Overall, our data show that GIRK channels play an important role in the regulation of sympathetic neurons excitability and that hiPSC-derived neurons provide an attractive in vitro tool for drug discovery to study sympathetic autoregulation and parasympathetic-sympathetic crosstalk. KEY POINTSO_LIhiPSC-sympathetic neurons recapitulate key cellular pathways of native counterparts C_LIO_LIThey express relevant receptors and ion channels involved in the inhibitory autoregulatory feedback and parasympathetic-sympathetic crosstalk C_LIO_LIUsing a combination of RT-qPCR and functional recordings we identified inwardly rectifying K+ channels as downstream effectors of both 2 adrenergic and M2 muscarinic receptors. We cross-validated our findings with a mouse transcriptomic dataset from thoracic sympathetic ganglia. C_LIO_LIOverall, our data suggest that hiPSC-sympathetic neurons can be employed as a human in vitro platform to study cellular pathways and for drug discovery purposes. C_LI O_FIG O_LINKSMALLFIG WIDTH=119 HEIGHT=200 SRC="FIGDIR/small/727423v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@14e37ddorg.highwire.dtl.DTLVardef@35c534org.highwire.dtl.DTLVardef@260837org.highwire.dtl.DTLVardef@e57af6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Summary of proposed modulation of sympathetic neuron activity via 2ARs and muscarinic receptors via GIRK channels Functional recordings showed that muscarinic receptors and 2 adrenergic receptors reduce neuronal excitability, this effect was mimicked by activation of inwardly rectifying K+ channels (GIRK). Blockade of GIRK abolished the effects of both types of receptors, demonstrating that they converge on GIRK as a common effector. The muscarinic response was blocked by pertussis toxin, indicating an involvement of Gi/o downstream of the receptor, consistent with the high expression of CHRM2 by RT-qPCR. C_FIG

neuroscience↗

bioRxiv2025

Genetic background influences the heterogeneous phenotypes driven by the MAFAS64F MODY variant in male mice

Pancreatic {beta}-cells require the coordinated expression of transcription factors such as MAFA to dynamically secrete insulin to maintain euglycemia. A naturally occurring mutation in MAFA (MAFAS64F) produces a long-lived variant protein which predisposes carriers to dichotomous conditions of either maturity (adult)-onset diabetes of the young (MODY) or hypoglycemia in a sex-dependent manner. Here we show that genetic background modulates disease penetrance in MafAS64F/+ male mice. Specifically, MafAS64F/+ males backcrossed to a C57/Bl6J ("C57") background prevented dysglycemia, while C57 MafAS64F/+ males bred one generation to an SJL/J background ("mixed") manifested overt diabetes, impaired insulin secretion, and accelerated {beta}-cell senescence. MafA protein levels, phosphorylation status, and target gene expression in C57 MafAS64F/+ male islets were more comparable to wildtype males. RNA sequencing of C57 MafAS64F/+ male islets revealed fewer differentially expressed genes than mixed background male islets, including transcriptional signatures of {beta}-cell senescence. In addition, retinoic acid signaling, another signature of cellular aging, was uniquely downregulated in C57 MafAS64F/+ male islets. Indeed, core retinoic acid signaling receptor RAR and known target genes were downregulated in C57 MafAS64F/+ male islets. CUT&RUN mapping revealed that MafA directly impacted retinoic acid receptor alpha Rara expression. In sum, these data show that genetic factors can impact unique pathways to modulate disease penetrance in mice modeling MAFA-MODY. Article HighlightsO_LIGenetic background in mice or ancestry in humans can profoundly influence diabetes susceptibility. C_LIO_LIWe asked whether diabetes penetrance in our robust mouse model of MAFA-MODY on a mixed genetic background was impacted when backcrossed to C57/Bl6J ("C57"). C_LIO_LIHere we show that C57 MafAS64F/+ males have wildtype glucose-sensing properties, compared to overt diabetes which could be reproducibly re-created on a mixed background. Further analysis disclosed more muted gene expression changes in C57 MafAS64F/+ male islets including unique downregulation of senescence and retinoic acid signaling. C_LIO_LIThese results illustrate the influence of genetic landscape on {beta}-cell function in response to a pathogenic MODY variant. C_LI

physiology↗

bioRxiv2025

The Cause of Most Common Antler Abnormality is Not a Fracture But an Osteomyelitis Like Disease the Pedunculitis Chronica Deformans

Climate change is increasing the incidence of certain diseases in wildlife, offering a deeper understanding of their underlying causes. Traditionally, the most common antler abnormalities have been attributed to trauma, based on their morphology. However, this explanation does not account for the epidemic-like spread of abnormalities in specific regions, suggesting that they might be a previously undescribed aspect of this anomaly. In fallow deer (Dama dama), using advanced medical diagnostic tools, we identified an osteomyelitis-like condition, Pedunculitis Chronica Deformans (PCD) which is also observed in other Cervidae. The incidence of this disease shows a strong correlation with the production of mycotoxins by molds that are becoming more prevalent with global warming. Mycotoxins can inhibit wound healing through scar formation after the antlers are cast, leading to the development of PCD. In this report we characterize PCD pathomorphology and introduce a scoring system to differentiate it from other deformities. Moreover, we argue that the most common anomalies such as fractures, antler losses, fatal meningoencephalitis and brain abscesses are complications of PCD. Our research underscores the potential of antlers to serve as biomarkers for mycotoxin exposure.

zoology↗

bioRxiv2024

Onco-fetal protein Nogo-A restricts human and mouse glioma vascularization and growth via VEGF-Notch-hippo-metabolic signaling

Glioblastoma is one of the most deadly human cancers characterized by high degrees of vascularization, but targeting its vasculature has resulted in very limited success so far. Angiogenesis, the growth of new blood vessels, is highly dynamic during brain development, enters a mostly quiescent state in the adult homeostatic brain, and is reactivated in vascular-dependent CNS diseases including brain tumors. In consequence, a better understanding of the relevance of the onco-fetal axis - describing the reactivation of fetal signaling programs in tumors - in endothelial- and perivascular cells of the human brain tumor vasculature harbors great translational potential, yet remains poorly defined. In development, neurovascular link (NVL) molecules guide both neuronal growth cones as well as capillary endothelial tip cells. Nogo-A is an NVL molecule known to inhibit axonal growth in the developing and adult CNS and to restrict angiogenesis during brain development, but its role in the mouse and human brain tumor vasculature along the onco-fetal axis remains unknown. Here, we characterize Nogo-A as an onco-fetal protein expressed in the neurovascular unit (NVU) in human fetal brains and human gliomas in vivo that negatively regulates sprouting angiogenesis and endothelial tip cells in glioma vascularization. The Nogo-A-specific Delta 20 domain restricts angiogenic sprouting and branching and promotes vascular normalization while inhibiting glioma growth in experimental gliomas. Moreover, Nogo-A expression in tumor cells negatively correlate/s with glioma malignancy in vivo. In vitro, Nogo-A Delta 20 reduced human brain- and brain tumor endothelial cell (HBMVEC, HBTMVEC) and human umbilical vein endothelial cell (HUVEC) spreading, migration, and sprouting, in a dose-dependent manner and inhibited filopodia extension glucose metabolism. Mechanistically, RNA sequencing of Nogo-A Delta 20-treated HBMVECs and HBTMVECs revealed Nogo-A Delta 20-induced positive regulation of the angiogenesis-inhibiting Dll4-Notch-pathway and inhibition of the angiogenesis-promoting VEGF-VEGFR and Hippo-YAP-TAZ pathways, whereas metabolomics and functional metabolic assays revealed Nogo-A Delta 20-induced negative regulation of endothelial glycolysis in HBMVECs and HBTMVECs. These findings characterize Nogo-A as an onco-fetal protein in the human glial brain tumor vasculature and identify Nogo-A Delta 20 signaling as an important negative regulator of human glioma vascularization and growth. Enhancing Nogo-A signaling may be an attractive alternative or combinatorial anti-angiogenic therapy to restrict human glioma/glioblastoma vascularization and growth.

neuroscience↗

bioRxiv2021

Label-free imaging of macrophage phenotypes and phagocytic activity in the human dermis in vivo using two-photon excited FLIM

Macrophages (M{Phi}s) are important immune effector cells that promote (M1 M{Phi}s) or inhibit (M2 M{Phi}s) inflammation and are involved in numerous physiological and pathogenic immune responses. Their precise role and relevance, however, is not fully understood because of the lack of non-invasive quantification methods. Here, we show that two-photon excited fluorescence lifetime imaging (TPE-FLIM), a label-free non-invasive method, can visualize M{Phi}s in human dermis in vivo. We demonstrate in vitro that human dermal M{Phi}s exhibit specific TPE-FLIM properties that distinguish them from the main components of the extracellular matrix and other dermal cells. We visualized M{Phi}s, their phenotypes and phagocytosis in the skin of healthy individuals in vivo using TPE-FLIM. Additionally, machine learning identified M1 and M2 M{Phi}s with a sensitivity of 0.88{+/-}0.04 and 0.82{+/-}0.03 and a specificity of 0.89{+/-}0.03 and 0.90{+/-}0.03, respectively. In clinical research, TPE-FLIM can advance the understanding of the role of M{Phi}s in health and disease.

biophysics↗

bioRxiv2021

Impaired lamin localization to the nuclear envelope is responsible for nuclear damage in LMNA mutant iPSC-derived cardiomyocytes

The LMNA gene encodes the nuclear envelope proteins Lamins A and C, which comprise a major part of the nuclear lamina, provide mechanical support to the nucleus, and participate in diverse intracellular signaling. LMNA mutations give rise to a collection of diseases called laminopathies, including dilated cardiomyopathy (LMNA-DCM) and muscular dystrophies. Although nuclear deformities are a hallmark of LMNA-DCM, the role of nuclear abnormalities in the pathogenesis of LMNA-DCM remains incompletely understood. Using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LMNA mutant patients and healthy controls, we show that LMNA mutant iPSC-CM nuclei have altered shape or increased size compared to healthy control iPSC-CM nuclei. The LMNA mutation exhibiting the most severe nuclear deformities, R249Q, additionally caused reduced nuclear stiffness and increased nuclear fragility. Importantly, for all cell lines, the degree of nuclear abnormalities corresponded to the degree of Lamin A/C and Lamin B1 mislocalization from the nuclear envelope. The mislocalization was likely due to altered assembly of Lamin A/C. Collectively, these results point to the importance of correct lamin assembly at the nuclear envelope in providing mechanical stability to the nucleus and suggest that defects in nuclear lamina organization may contribute to the nuclear and cellular dysfunction in LMNA-DCM.

cell biology↗

bioRxiv2021

Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.

pathology↗

bioRxiv2021

PolyQ expansion does not alter the Huntingtin-HAP40 complex

The abnormal amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch located at the HTT N-terminus, which renders it aggregation-prone by unknown mechanisms. Here we investigated the effects of polyQ expansion on HTT in a complex with its stabilizing interaction partner huntingtin-associated protein 40 (HAP40). Surprisingly, our comprehensive biophysical, crosslinking mass spectrometry and cryo-EM experiments revealed no major differences in the conformation of HTT-HAP40 complexes of various polyQ length, including 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients) and 128QHTT-HAP40 (extreme polyQ length). Thus, HTT polyQ expansion does not alter the global structure of HTT when associated with HAP40.

biophysics↗

bioRxiv2019

Alteration of cardiolipin-dependent mitochondrial coupling in muscle protects against obesity

The tubular shape of mitochondrial cristae depends upon a specific composition of the inner mitochondrial membrane, including cardiolipin that allows strong curvature and promotes optimal organization of ATP synthase. Here we identify Hacd1, which encodes an enzyme involved in very long chain fatty acid biosynthesis, as a key regulator of composition, structure and functional properties of mitochondrial membranes in muscle. In Hacd1-deficient mice, the reduced cardiolipin content was associated with dilation of cristae and caused defective phosphorylating respiration, characterized by absence of proton leak and oxidative stress.\n\nThe skeletal muscle-specific mitochondrial coupling defect produced a global elevation in basal energy expenditure with increased carbohydrate and lipid catabolism, despite decreased muscle mass and locomotor capacities. Mice were protected against diet-induced obesity despite reduced muscle activity, providing an in vivo proof of concept that reducing mitochondrial coupling efficiency in skeletal muscle might be an actionable mechanism in metabolic disease conditions.

cell biology↗

bioRxiv2019

Photoactivation of olfactory sensory neurons does not affect action potential conduction in individual trigeminal sensory axons innervating the rodent nasal cavity

Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we focused on potential interactions between olfactory and trigeminal signaling in the nasal cavity. We first used a forced choice paradigm to ascertain whether trigeminal and olfactory stimuli could influence behavior in mice. Mice avoided water sources associated with volatile TRPV1 and TRPA1 irritants, however, this aversion was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioral effect we recorded from single trigeminal sensory axons innervating the nasal epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in a mouse line expressing channel-rhodopsin under the olfactory marker protein. During photoactivation of olfactory sensory neurons there was no modulation of action potential conduction in individual trigeminal axons. Similarly, no evidence was found for trigeminal axon collateral branching that might serve as a conduit for cross-talk between the olfactory epithelium and olfactory dura mater. Using direct assessment of trigeminal signals emanating from the mouse nasal cavity we see no evidence for paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the nasal cavity.

neuroscience↗

bioRxiv2018

The Aryl Hydrocarbon Receptor senses the Henna pigment Lawsone and mediates Yin-Yang effects on skin homeostasis

As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. Tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes.

cell biology↗