Kiavash Movahedi

Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer’s disease reduced local amyloid-β amounts and C1q deposition and partially rescued synapse loss. Combining spatial transcriptomics, live cell tracking, and super-resolution microscopy, we identified association of antibody-secreting B-lineage cells in the adult hippocampus with activity-dependent, C1q-mediated synapse loss under physiological conditions. Together, these findings link neuronal hyperactivity to C1q-mediated synapse loss in the adult brain and implicate immunoglobulins as players in this process.

The pivotal role of tumor infiltrating myeloid cells in lung cancer composition and response to therapy is universally recognized. Nevertheless, their main cradle being the bone marrow (BM), remains vastly understudied owing to the spatiotemporal complexity of hematopoiesis and its hard to access anatomical location. Therefore, the BM niche of lung cancer subjects remains understudied which is why we integrated transcriptional and translational single-cell profiling, ELISA and two-photon microscopy to characterize the medullary hematopoietic compartment in orthotopic lung cancer-bearing mice with validation in human non-small cell lung cancer (NSCLC) samples. In brief we found that lung cancer remotely alters the entire hematopoietic process resulting in higher levels of hematopoietic stem cells (HSCs), myeloid and lymphoid multipotent progenitors (MPPs) and downstream predominance of Granulocyte Monocyte Progenitors (GMP), early Granulocyte Progenitors (GP) and Common Monocyte Progenitors (cMoP) at the expense of mature neutrophils and B cells. Furthermore, a significant increase in the expression and secretion of S100A9 and Lipocalin-2 (LCN2), was characteristic across the entire hematopoietic trajectory in lung cancer-bearing mice and patients. In vivo inhibition of S100A9 with Tasquinimod reduced tumor growth, irrespective of its combination with immunotherapy. In addition, it altered the secretion profile of S100A9 but also LCN2 in the BM, suggesting that S100A9 serves as an upstream regulator of LCN2 and holds therapeutic premise to treat immunotherapy refractory lung cancer.

Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain^1,2,3,4. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD^1,5,6,7. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut–brain axis remain elusive. Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD^8,9. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut–brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.

Aims/hypothesis Regenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularisation of the endocrine pancreas could trigger mouse beta cell proliferation. Methods A doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularisation. In this model, vascular endothelial growth factor (VEGF)-A signalling within pancreatic islets is antagonised through beta cell-specific overexpression of a VEGF-A decoy receptor, soluble fms-like tyrosine kinase 1 (sFLT1). Cessation of sFLT1 overexpression was induced by DOX withdrawal. sFLT1 expression, vessel kinetics and beta cell proliferation upon DOX administration and withdrawal were analysed using quantitative RT-PCR and immunostaining. Single-cell RNA-seq was used to investigate the effects on the islet cells’ transcriptome and perform pathway enrichment analysis. RIP-rtTA;TetO-GFP mice were studied in parallel to assess the dependency of cell cycle induction on vessel manipulation. Additionally, in vitro experiments were conducted to further elucidate and validate our in vivo findings. Results Serendipitously, we discovered that sFLT1 overexpression in beta cells induces endoplasmic reticulum (ER) stress and activates proliferation-associated pathways. Upon cessation of sFLT1 overexpression, ER stress decreased and beta cell proliferation was promoted independently of vessel recovery, as shown by cumulative BrdU labelling over 7 days (mean ± SEM vs control: 14.3 ± 1.3% vs 5.2 ± 0.6%) during the DOX withdrawal period. Transient GFP overexpression also induced ER stress and a subsequent reduction thereof resulted in increased beta cell proliferation (mean ± SEM vs control: 7.2 ± 0.4% vs 5.1 ± 0.5%). Chemical, transient induction of ER stress in vitro by ER-stress-inducing compounds reproduced this beta cell cycling response, as assessed by cumulative EdU labelling during a 3 day washout period (mean ± SEM vs control: 2.6 ± 0.4% vs 0.8 ± 0.2% for thapsigargin and 3.8 ± 0.9% vs 1.0 ± 0.2% for tunicamycin), which further increased under high-glucose conditions when islets were exposed to thapsigargin (mean ± SEM vs control: 9.0 ± 1.2% vs 2.0 ± 0.4%). Conclusions/interpretation Our findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells. Data and code availability The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443. Graphical Abstract

Human pluripotent stem cells (hPSC) are increasingly used in clinical trials, with retinal pigment epithelium (RPE) being among the most transplanted cell types. However, hPSC frequently acquire chromosomal abnormalities, whose impact on differentiation and transplant safety is incompletely understood. In this work, we investigate how aneuploidy influences the progression of hPSC through undirected RPE differentiation. Large-scale omics analysis of genetically normal hPSC cultures reveals pervasive low-grade mosaicism, with 3–6% of cells carrying different aneuploidies. During undirected differentiation, all aneuploid cells are lost except those with a gain of chromosome arm 1q. These cells differentiate efficiently only when co-cultured with wild-type cells, which promote neural differentiation through paracrine signals that 1q-gain cells are uniquely receptive to. This interaction enables 1q-gain cells not only to persist but to eventually dominate the culture, owing to their competitive advantage.

Large peritoneal macrophages (LPMs) play a role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogens. A third of the LPMs express the surface receptor VSIG4, but it is unclear whether these cells differ from their VSIG4‐negative counterparts and perform dedicated functions. We demonstrate that VSIG4⁺, but not VSIG4⁻, LPMs are in the majority derived from embryonal precursors, and their occurrence is largely independent of sex and microbiota but increases with age. Although their transcriptome and surface proteome are indistinguishable from VSIG4⁻ LPMs at steady‐state, VSIG4⁺ LPMs are superior in phagocytosing S. aureus bioparticles and colorectal carcinoma (CRC) cells. Anti‐VSIG4 nanobody constructs that are ADCC‐enabled allowed a selective elimination of the VSIG4⁺ LPM subset without affecting overall LPM abundance. This strategy uncovered a role for VSIG4⁺ LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing CRC outgrowth in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4⁺ LPMs in infectious and oncological diseases in the peritoneal cavity.