Publications

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43 Publications visible to you, out of a total of 43
Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Abstract (Expand)

BACKGROUND: Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle … cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. METHODS: Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient-specific induced pluripotent stem cell line was compared to a CRISPR/Cas9-edited isogenic control line. RESULTS: The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two-dimensional and three-dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration-competent satellite-like cell pool. Tissue-engineered muscle exhibits organotypic maturation and function (up to 5.7 +/- 0.5 mN tetanic twitch tension at 100 Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107 +/- 2 to 75 +/- 4 ms (P < 0.05) and from 146 +/- 6 to 100 +/- 6 ms (P < 0.05), respectively. Satellite-like cells could be documented as largely quiescent PAX7(+) cells (75 +/- 6% Ki67(-) ) located adjacent to muscle fibres confined under a laminin-containing basal membrane. Activation of the engineered satellite-like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57 +/- 8% of the pre-injury force 21 days post-injury (P < 0.05 compared to Day 2 post-injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (-35 +/- 7%, P < 0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175 +/- 14 ms, P < 0.05 vs. gene-edited control) and relaxation (238 +/- 22 ms, P < 0.05 vs. gene-edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM. CONCLUSIONS: We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair.

Authors: M. Shahriyari, M. R. Islam, S. M. Sakib, M. Rinn, A. Rika, D. Kruger, L. Kaurani, V. Gisa, M. Winterhoff, H. Anandakumar, O. Shomroni, M. Schmidt, G. Salinas, A. Unger, W. A. Linke, J. Zschuntzsch, J. Schmidt, R. Bassel-Duby, E. N. Olson, A. Fischer, W. H. Zimmermann, M. Tiburcy

Date Published: 19th Oct 2022

Publication Type: Journal Article

Brain injury environment critically influences the connectivity of transplanted neurons

Abstract (Expand)

Cell transplantation is a promising approach for the reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse … cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration, and scar formation, as in traumatic brain injury (TBI). To elucidate this, we transplanted cells from the embryonic mouse cerebral cortex into TBI-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative monosynaptic rabies virus (RABV) tracing unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact and inflamed brain versus exuberant after TBI. In the latter, the initial overshoot is followed by pruning, with only a few input neurons persisting at 3 months. Proteomic profiling identifies candidate molecules for regulation of the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits.

Authors: Sofia Grade, Judith Thomas, Yvette Zarb, Manja Thorwirth, Karl-Klaus Conzelmann, Stefanie M. Hauck, Magdalena Götz

Date Published: 10th Jun 2022

Publication Type: Journal Article

The lung microbiome regulates brain autoimmunity.

Abstract (Expand)

Lung infections and smoking are risk factors for multiple sclerosis, a T-cell-mediated autoimmune disease of the central nervous system(1). In addition, the lung serves as a niche for the disease-inducing … T cells for long-term survival and for maturation into migration-competent effector T cells(2). Why the lung tissue in particular has such an important role in an autoimmune disease of the brain is not yet known. Here we detected a tight interconnection between the lung microbiota and the immune reactivity of the brain. A dysregulation in the lung microbiome significantly influenced the susceptibility of rats to developing autoimmune disease of the central nervous system. Shifting the microbiota towards lipopolysaccharide-enriched phyla by local treatment with neomycin induced a type-I-interferon-primed state in brain-resident microglial cells. Their responsiveness towards autoimmune-dominated stimulation by type II interferons was impaired, which led to decreased proinflammatory response, immune cell recruitment and clinical signs. Suppressing lipopolysaccharide-producing lung phyla with polymyxin B led to disease aggravation, whereas addition of lipopolysaccharide-enriched phyla or lipopolysaccharide recapitulated the neomycin effect. Our data demonstrate the existence of a lung-brain axis in which the pulmonary microbiome regulates the immune reactivity of the central nervous tissue and thereby influences its susceptibility to autoimmune disease development.

Authors: L. Hosang, R. C. Canals, F. J. van der Flier, J. Hollensteiner, R. Daniel, A. Flugel, F. Odoardi

Date Published: 25th Feb 2022

Publication Type: Journal Article

Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain

Abstract (Expand)

The oligodendrocyte progenitors (OPCs) are at the front of the glial reaction to the traumatic brain injury. However, regulatory pathways steering the OPC reaction as well as the role of reactive OPCs … remain largely unknown. Here, we compared a long-lasting, exacerbated reaction of OPCs to the adult zebrafish brain injury with a timely restricted OPC activation to identify the specific molecular mechanisms regulating OPC reactivity and their contribution to regeneration. We demonstrated that the influx of the cerebrospinal fluid into the brain parenchyma after injury simultaneously activates the toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways, leading to increased OPC proliferation and thereby exacerbated glial reactivity. These pathways were critical for long-lasting OPC accumulation even after the ablation of microglia and infiltrating monocytes. Importantly, interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated reactive gliosis, increased new neuron recruitment, and improved tissue restoration.

Authors: Rosario Sanchez-Gonzalez, Christina Koupourtidou, Tjasa Lepko, Alessandro Zambusi, Klara Tereza Novoselc, Tamara Durovic, Sven Aschenbroich, Veronika Schwarz, Christopher T. Breunig, Hans Straka, Hagen B. Huttner, Martin Irmler, Johannes Beckers, Wolfgang Wurst, Andreas Zwergal, Tamas Schauer, Tobias Straub, Tim Czopka, Dietrich Trümbach, Magdalena Götz, Stefan H. Stricker, Jovica Ninkovic

Date Published: 2nd Feb 2022

Publication Type: Journal Article

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery

Abstract

Not specified

Authors: Horst Penkert, Alix Bertrand, Vini Tiwari, Stephan Breimann, Stephan A. Müller, Paul M. Jordan, Mathias J. Gerl, Christian Klose, Ludovico Cantuti-Castelvetri, Mar Bosch-Queralt, Ilya Levental, Stefan F. Lichtenthaler, Oliver Werz, Mikael Simons

Date Published: 1st Oct 2021

Publication Type: Journal Article

Biallelic variants in YRDC cause a developmental disorder with progeroid features.

Abstract (Expand)

The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies … have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t(6)A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient's dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.

Authors: J. Schmidt, J. Goergens, T. Pochechueva, A. Kotter, N. Schwenzer, M. Sitte, G. Werner, J. Altmuller, H. Thiele, P. Nurnberg, J. Isensee, Y. Li, C. Muller, B. Leube, H. C. Reinhardt, T. Hucho, G. Salinas, M. Helm, R. D. Jachimowicz, D. Wieczorek, T. Kohl, S. E. Lehnart, G. Yigit, B. Wollnik

Date Published: 22nd Sep 2021

Publication Type: Journal Article

Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2

Abstract

Not specified

Authors: J. Kempf, K. Knelles, B.A. Hersbach, D. Petrik, T. Riedemann, V. Bednarova, A. Janjic, T. Simon-Ebert, W. Enard, P. Smialowski, M. Götz, G. Masserdotti

Date Published: 1st Jul 2021

Publication Type: Journal Article

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