Publications

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43 Publications visible to you, out of a total of 43
Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity

Abstract

Not specified

Authors: Michael Hiltensperger, Eduardo Beltrán, Ravi Kant, Sofia Tyystjärvi, Gildas Lepennetier, Helena Domínguez Moreno, Isabel J. Bauer, Simon Grassmann, Sebastian Jarosch, Kilian Schober, Veit R. Buchholz, Selin Kenet, Christiane Gasperi, Rupert Öllinger, Roland Rad, Andreas Muschaweckh, Christopher Sie, Lilian Aly, Benjamin Knier, Garima Garg, Ali M. Afzali, Lisa Ann Gerdes, Tania Kümpfel, Sören Franzenburg, Naoto Kawakami, Bernhard Hemmer, Dirk H. Busch, Thomas Misgeld, Klaus Dornmair, Thomas Korn

Date Published: 7th Jun 2021

Publication Type: Journal Article

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

Abstract

[Figure: see text].

Authors: J. Peper, D. Kownatzki-Danger, G. Weninger, F. Seibertz, J. R. D. Pronto, H. Sutanto, D. Pacheu-Grau, R. Hindmarsh, S. Brandenburg, T. Kohl, G. Hasenfuss, M. Gotthardt, E. A. Rog-Zielinska, B. Wollnik, P. Rehling, H. Urlaub, J. Wegener, J. Heijman, N. Voigt, L. Cyganek, C. Lenz, S. E. Lehnart

Date Published: 19th Mar 2021

Publication Type: Journal Article

Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation

Abstract

Not specified

Authors: Mehrnoosh Jafari, Adrian-Minh Schumacher, Nicolas Snaidero, Emily M. Ullrich Gavilanes, Tradite Neziraj, Virág Kocsis-Jutka, Daniel Engels, Tanja Jürgens, Ingrid Wagner, Juan Daniel Flórez Weidinger, Stephanie S. Schmidt, Eduardo Beltrán, Nellwyn Hagan, Lisa Woodworth, Dimitry Ofengeim, Joseph Gans, Fred Wolf, Mario Kreutzfeldt, Ruben Portugues, Doron Merkler, Thomas Misgeld, Martin Kerschensteiner

Date Published: 25th Jan 2021

Publication Type: Journal Article

Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

Abstract (Expand)

BACKGROUND: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, … intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. METHODS: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. RESULTS: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. CONCLUSIONS: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Authors: U. Hanses, M. Kleinsorge, L. Roos, G. Yigit, Y. Li, B. Barbarics, I. El-Battrawy, H. Lan, M. Tiburcy, R. Hindmarsh, C. Lenz, G. Salinas, S. Diecke, C. Muller, I. Adham, J. Altmuller, P. Nurnberg, T. Paul, W. H. Zimmermann, G. Hasenfuss, B. Wollnik, L. Cyganek

Date Published: 15th Sep 2020

Publication Type: Journal Article

Extracellular Vesicles Derived from Neural Progenitor Cells--a Preclinical Evaluation for Stroke Treatment in Mice.

Abstract (Expand)

Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application … of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell-induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression.

Authors: X. Zheng, L. Zhang, Y. Kuang, V. Venkataramani, F. Jin, K. Hein, M. P. Zafeiriou, C. Lenz, W. Moebius, E. Kilic, D. M. Hermann, M. S. Weber, H. Urlaub, W. H. Zimmermann, M. Bahr, T. R. Doeppner

Date Published: 4th May 2020

Publication Type: Journal Article

CRISPLD1: a novel conserved target in the transition to human heart failure.

Abstract (Expand)

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are … lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca(2+) cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca(2+) handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca(2+)-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca(2+) regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.

Authors: S. Khadjeh, V. Hindmarsh, F. Weber, L. Cyganek, R. O. Vidal, S. Torkieh, K. Streckfuss-Bomeke, D. Lbik, M. Tiburcy, B. A. Mohamed, S. Bonn, K. Toischer, G. Hasenfuss

Date Published: 7th Mar 2020

Publication Type: Journal Article

Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

Abstract (Expand)

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked … whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB–dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.

Authors: Maria Inês Cunha, Minhui Su, Ludovico Cantuti-Castelvetri, Stephan A. Müller, Martina Schifferer, Minou Djannatian, Ioannis Alexopoulos, Franziska van der Meer, Anne Winkler, Tjakko J. van Ham, Bettina Schmid, Stefan F. Lichtenthaler, Christine Stadelmann, Mikael Simons

Date Published: 20th Feb 2020

Publication Type: Journal Article

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