Biology subjects

Marx, N.

Publications and source records attributed to Marx, N..

5 recordsLinked to original sources

bioRxiv2026

Single-cell characterization of human periodontal ligament (PDL) cells reveals uniformly mesenchymal populations in matched maxilla and mandible pairs from four donors

The periodontal ligament (PDL) is a mechanically active connective tissue whose fibroblasts and resident progenitor cells drive tooth support, remodeling, and regeneration. Although PDL cell populations are known to be heterogeneous, the composition of expanded primary PDL cultures and the extent to which anatomical origin shapes their transcriptome remain incompletely defined. Here we applied single-cell RNA sequencing to cultured primary PDL cells isolated from matched upper (maxilla) and lower (mandible) jaw sites of four donors, yielding 43,423 cells that were integrated across donors and analyzed by unsupervised clustering. The expanded cultures were uniformly mesenchymal and fibroblastic, essentially devoid of endothelial and immune signatures, and resolved into ten functionally distinct fibroblast substates rather than discrete cell types, including proliferating, collagen- and extracellular-matrix-high, contractile, and progenitor-like populations. Donor identity was the dominant source of transcriptional variation, with several substates restricted to individual donors. A donor-controlled comparison of maxilla versus mandible revealed only a small set of differentially expressed genes, headed by craniofacial positional-identity transcription factors (PITX1 higher in the mandible; BARX1, ALX1, and NKX6-1 higher in the maxilla), indicating that cultured PDL cells retain embryonic positional memory. In contrast, curated wound-healing gene modules did not differ significantly between jaws, and the transcriptional data therefore did not support the clinical impression of faster healing in the maxilla, suggesting that the healing asymmetry more likely reflects vascular, mechanical, and inflammatory signaling factors acting beyond the steady-state transcriptome. These findings characterize the cellular composition of expanded PDL cultures and identify positional identity as the principal jaw-dependent transcriptional feature.

genomics↗

bioRxiv2025

The role of Platelet-derived growth factor (PDGF) in uremic vascular calcification.

Vascular calcification is common in chronic kidney disease (CKD), contributing to increased cardiovascular morbidity and mortality. One of the proposed mechanisms of driving vascular calcification is a phenotypic switch of vascular smooth muscle cells (VSMCs). The platelet-derived growth factors (PDGFs) and their receptors (PDGFRs), particularly PDGFR-{beta}, were shown to modulate the VSMC phenotype. However, their role in uremic vascular calcification remained unclear. We adapted an ex vivo calcification model using murine aortas to simulate uremic conditions. Compared to control conditions, incubation with hemodialysate from CKD patients or using aortas from CKD animals both resulted in significantly increased PDGFR-{beta} phosphorylation and vascular calcification. Inhibition of PDGF signaling using soluble PDGFR-{beta} or the small molecule tyrosine kinase inhibitor imatinib significantly reduced uremic calcification and enhanced vascular elasticity. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-{beta}. The aortas of these mice exhibited significantly increased vascular calcification ex vivo, which was further aggravated by uremic conditions. We established an in vivo model of accelerated vascular calcification and CKD in the transgenic mice, showing significantly aggravated vascular calcification and phenotypic switching of VSMCs compared to non-transgenic littermates. Finally, increased expression of phosphorylated PDGFR-{beta} and a VSMC phenotypic switching were detected in human arteries from patients with CKD compared to those without CKD. In conclusion, PDGFR-{beta} contributes to CKD-associated vascular calcification, representing a potential novel therapeutic target.

systems biology↗

bioRxiv2024

Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration

Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally, in vivo activation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.

immunology↗

bioRxiv2024

Mdivi-1 affects neuronal activity by inhibition of Complex I and respiratory supercomplex assembly

Several human diseases, including cancer and neurodegeneration, are associated with excessive mitochondrial fragmentation. In this context, mitochondrial division inhibitor (Mdivi-1) has been tested as a therapeutic to block the fission-related protein dynamin-like protein-1 (Drp1). Recent studies suggest that Mdivi-1 interferes with mitochondrial bioenergetics. Here we show that the molecular mechanism of Mdivi-1 is based on inhibition of complex I at the IQ site. This leads to the destabilization of complex I, impairs the assembly of N- and Q-respirasomes and is associated with increased ROS production. The result is a reduced efficiency of ATP generation. Second, the calcium homeostasis of cells is impaired, which severely affects the electrical activity of neurons. Given the results presented here, a potential therapeutic application of Mdivi-1 is challenging because of its impact on synaptic activity. Similar to the Complex I inhibitor rotenone, Mdivi-1 may lead to neurodegenerative effects in the long term. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/577160v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1bffc82org.highwire.dtl.DTLVardef@15ae3b5org.highwire.dtl.DTLVardef@1ba3a5org.highwire.dtl.DTLVardef@94cfc0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIMdivi-1 inhibits respiratory complex I at the IQ-site C_LIO_LIInhibition destabilizes complex I and reduces supercomplex formation C_LIO_LIMitochondrial ATP levels decrease C_LIO_LICa2+ metabolism is affected C_LIO_LINeuronal activity is compromised C_LI

cell biology↗

bioRxiv2021

Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell epitope mapping

The current COVID-19 pandemic represents a global challenge. A better understanding of the immune response against SARS-CoV-2 is key to unveil the differences in disease severity and to develop future vaccines targeting novel SARS-CoV-2 variants. Feature barcode technology combined with CITE-seq antibodies and DNA-barcoded peptide-MHC I Dextramer reagents enabled us to identify relevant SARS-CoV-2-derived epitopes and compare epitope-specific CD8+ T cell populations between mild and severe COVID-19. We identified a strong CD8+ T cell response against an S protein-derived epitope. CD8+ effector cells in severe COVID-19 displayed hyperactivation, T cell exhaustion and were missing characteristics of long-lived memory T cells. We identify A*0101 WTAGAAAYY as an immunogenic CD8+ T cell epitope with the ability to drive clonal expansion. We provide an in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection which will be relevant for the development of molecular and targeted therapies and potential adjustments of vaccination strategies.

immunology↗