Biology subjects

Klingel, K.

Publications and source records attributed to Klingel, K..

3 recordsLinked to original sources

bioRxiv2026

Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium

Myocardial fibrosis is a common end point of acute and chronic cardiovascular injury, yet the spatially organized fibroblast (Fb) and immune-cell states that sustain fibrotic remodeling across etiologies remain incompletely defined. We applied cyclic in situ hybridization (cISH)-based spatial transcriptomics to myocardial biopsies from patients with acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), postviral myocardial fibrosis (PVMF), and systemic sclerosis associated primary heart involvement (SSc-pHI). CODEX-based protein imaging provided orthogonal support for cell subpopulations and cellular neighborhoods. Spatially informed clustering identified six Fb subpopulations: COL1A1hi/POSTNhi, NOTCH3+, TIMP1hi, GSNhi/DCNhi, AP1hi Fbs, and myofibroblasts. COL1A1hi/POSTNhi and NOTCH3+ Fbs were enriched in AMI, whereas GSNhi/DCNhi Fbs and myofibroblasts predominated in chronic fibrotic remodeling. These subpopulations displayed distinct extracellular matrix, inflammatory, and vasoregulatory programs. Infarction-associated reparative niches were enriched in COL1A1hi/POSTNhi or NOTCH3+ Fbs and SPP1+ or APOE+ macrophages (M{Phi}), whereas chronic fibroinflammatory niches were enriched in GSNhi/DCNhi or AP1hi Fbs or myofibroblasts with C1Q+ M{Phi} and plasma cells. The GSNhi/DCNhi Fb niche marked areas of subendocardial fibrosis, whereas the AP1hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1hi/POSTNhi Fb state characteristic of infarct scar formation was present at higher frequency than in other chronic entities and was individually associated with cardiac dysfunction, whereas the chronic GSNhi/DCNhi Fb niche was associated with the extent of interstitial fibrosis and anti-topoisomerase I autoantibodies. These data show that human myocardial fibrosis is organized into spatially distinct Fb subpopulations that assemble into context-specific fibroinflammatory niches across chronic fibrotic remodeling and repair after AMI.

cell biology↗

bioRxiv2021

A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

biochemistry↗

bioRxiv2021

mTOR-activating mutations in RRAGD cause kidney tubulopathy and cardiomyopathy (KICA) syndrome

BackgroundOver the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, {+/-}20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM). MethodsWhole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro. ResultsIn 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro, ConclusionsOur findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function. SIGNIFICANCE STATEMENTHere, we report on heterozygous variants in RRAGD in patients with profound hypomagnesemia, renal salt wasting, nephrocalcinosis, and dilated cardiomyopathy. The identified RagD variants induce a constitutive activation of mTOR signaling in vitro. These findings not only establish a novel monogenic disorder of the kidney tubule, but demonstrate the essential role of mTOR signaling for distal tubular electrolyte handling and cardiac function.

genetics↗