ORCID Profile
0000-0001-7175-5062
Current Organisation
University Medical Center Hamburg-Eppendorf
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Publisher: Elsevier BV
Date: 11-2020
Publisher: Cold Spring Harbor Laboratory
Date: 18-11-2019
DOI: 10.1101/845941
Abstract: Kidney transplantation is the preferred renal replacement therapy available. Yet, the biological processes during and after kidney transplantation and how they translate into the overall functional graft outcome are insufficiently understood. Recent developments in the field of extracellular vesicle research allow the deeper exploitation of this non-invasive source. We separated small urinary extracellular vesicles (suEVs) throughout the course of living donor kidney transplantation. SuEVs were collected longitudinally from both the donor and the recipient in 22 living donor kidney transplantations. Unbiased proteomic analysis revealed specific temporal patterns of suEV proteins indicative of the cellular processes involved in the allograft’s response after transplantation with proteins playing a role in complement activation being among the most dynamically regulated components. Using a leave-one-out cross validation model, we identified potential prognostic markers of kidney function at 1 year after transplantation. One of the proteins identified – phosphoenol pyruvate carboxykinase (PCK2) – could be confirmed in an independent validation cohort of another 22 donor-recipient pairs using targeted mass spectrometry. This study sheds the light on early molecular processes during the course of kidney transplantation and shows the future potential of suEVs as a source of biomarkers in this setting. The data set is provided as a unique resource directly accessible through an online tool that allows dynamic interrogation of this first comprising suEV proteome atlas after kidney transplantation. This study represents the first atlas of the proteomic changes in small urinary extracellular vesicles throughout living donor kidney transplantation identifying PCK2 abundance as a biomarker for renal function 12 months after transplantation
Publisher: Wiley
Date: 20-07-2021
DOI: 10.1111/TID.13685
Publisher: Springer Science and Business Media LLC
Date: 14-08-2023
DOI: 10.1038/S41467-023-39740-7
Abstract: Kidney organoids are a promising model to study kidney disease, but their use is constrained by limited knowledge of their functional protein expression profile. Here, we define the organoid proteome and transcriptome trajectories over culture duration and upon exposure to TNFα, a cytokine stressor. Older organoids increase deposition of extracellular matrix but decrease expression of glomerular proteins. Single cell transcriptome integration reveals that most proteome changes localize to podocytes, tubular and stromal cells. TNFα treatment of organoids results in 322 differentially expressed proteins, including cytokines and complement components. Transcript expression of these 322 proteins is significantly higher in in iduals with poorer clinical outcomes in proteinuric kidney disease. Key TNFα-associated protein (C3 and VCAM1) expression is increased in both human tubular and organoid kidney cell populations, highlighting the potential for organoids to advance biomarker development. By integrating kidney organoid omic layers, incorporating a disease-relevant cytokine stressor and comparing with human data, we provide crucial evidence for the functional relevance of the kidney organoid model to human kidney disease.
Publisher: American Society for Clinical Investigation
Date: 10-01-2023
Publisher: Elsevier BV
Date: 04-2019
Publisher: American Society for Clinical Investigation
Date: 06-2021
DOI: 10.1172/JCI135821
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-02-2021
DOI: 10.1126/SCIIMMUNOL.ABF6692
Abstract: Tissue-resident memory-like T H 17 cells are clonally expanded in bronchoalveolar lavage fluid of patients with severe COVID-19.
Publisher: Frontiers Media SA
Date: 16-04-2018
Publisher: Springer Science and Business Media LLC
Date: 24-07-2019
DOI: 10.1038/S41467-019-11013-2
Abstract: The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from in iduals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and β1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.
Publisher: American Society for Clinical Investigation
Date: 19-09-2019
Publisher: Springer Science and Business Media LLC
Date: 28-03-2022
DOI: 10.1038/S42255-022-00552-6
Abstract: Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae 1 . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated 2,3 . Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy s les obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy s les, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.
Publisher: American Society for Clinical Investigation
Date: 08-04-2021
Publisher: EMBO
Date: 14-01-2020
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.KINT.2019.02.034
Abstract: Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2015
DOI: 10.1038/ONC.2015.335
Publisher: Springer Science and Business Media LLC
Date: 28-01-2023
DOI: 10.1038/S41467-023-36068-0
Abstract: Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: American Society for Clinical Investigation
Date: 06-2023
DOI: 10.1172/JCI157782
Publisher: Springer Science and Business Media LLC
Date: 06-08-2018
DOI: 10.1007/S00432-018-2724-3
Abstract: Cell fate determinants Scrib and Llgl1 influence self-renewal capacity of hematopoietic stem cells (HSCs). Scrib-deficient HSCs are functionally impaired and lack sufficient repopulation capacity during serial transplantation and stress. In contrast, loss of Llgl1 leads to increased HSC fitness, gain of self-renewal capacity and expansion of the stem cell pool. Here, we sought to assess for shared and unique molecular functions of Llgl1 and Scrib by analyzing their interactome in hematopoietic cells. Interactome analysis was performed by affinity purification followed by mass spectrometry. Motility, migration and adhesion were assessed on primary murine HSCs, which were isolated by FACS sorting following conditional deletion of Scrib or Llgl1, respectively. Imaging of Scrib-deficient HSCs was performed by intravital 2-photon microscopy. Comparison of Scrib and Llgl1 interactome analyses revealed involvement in common and unique cellular functions. Migration and adhesion were among the cellular functions connected to Scrib but not to Llgl1. Functional validation of these findings confirmed alterations in cell adhesion and migration of Scrib-deficient HSCs in vitro and in vivo. In contrast, genetic inactivation of Llgl1 did not affect adhesion or migratory capacity of hematopoietic stem cells. Our data provide first evidence for an evolutionarily conserved role of the cell fate determinant Scrib in HSC adhesion and migration in vitro and in vivo, a unique function that is not shared with its putative complex partner Llgl1.
Publisher: Springer Science and Business Media LLC
Date: 04-2023
DOI: 10.1038/S41565-023-01328-Z
Abstract: Expansion microscopy physically enlarges biological specimens to achieve nanoscale resolution using diffraction-limited microscopy systems 1 . However, optimal performance is usually reached using laser-based systems (for ex le, confocal microscopy), restricting its broad applicability in clinical pathology, as most centres have access only to light-emitting diode (LED)-based widefield systems. As a possible alternative, a computational method for image resolution enhancement, namely, super-resolution radial fluctuations (SRRF) 2,3 , has recently been developed. However, this method has not been explored in pathology specimens to date, because on its own, it does not achieve sufficient resolution for routine clinical use. Here, we report expansion-enhanced super-resolution radial fluctuations (ExSRRF), a simple, robust, scalable and accessible workflow that provides a resolution of up to 25 nm using LED-based widefield microscopy. ExSRRF enables molecular profiling of subcellular structures from archival formalin-fixed paraffin-embedded tissues in complex clinical and experimental specimens, including ischaemic, degenerative, neoplastic, genetic and immune-mediated disorders. Furthermore, as ex les of its potential application to experimental and clinical pathology, we show that ExSRRF can be used to identify and quantify classical features of endoplasmic reticulum stress in the murine ischaemic kidney and diagnostic ultrastructural features in human kidney biopsies.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-12-2018
Abstract: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. We used mouse models, including DNA methyltransferase ( Dnmt1, Dnmt3a, and Dnmt3b ) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b ) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1 -deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.
Publisher: American Society for Clinical Investigation
Date: 02-05-2022
DOI: 10.1172/JCI147253
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-08-2020
DOI: 10.1126/SCIIMMUNOL.ABA4163
Abstract: CD4 + T RM 17 cells become activated by inflammatory cytokines to produce IL-17A and thereby promote autoimmunity.
Publisher: Informa UK Limited
Date: 02-01-2016
No related grants have been discovered for Tobias B. Huber.