Biology subjects

Kamp, J.-C.

Publications and source records attributed to Kamp, J.-C..

3 recordsLinked to original sources

bioRxiv2026

iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept

Pulmonary arterial hypertension (PAH) is a potentially fatal disease characterized by obliterative remodeling of distal pulmonary arteries, commonly associated with bone morphogenetic receptor type 2 (BMPR2) gene mutations. In patients with PAH, sotatercept, an activin signaling inhibitor, improves hemodynamics and outcomes, but clinical responses vary and sometimes occur within weeks, suggesting additional mechanisms beyond its anti-proliferative, pro-apoptotic and anti-remodeling effects. Using patient-specific induced pluripotent stem cell-derived smooth muscle cells (iSMCs) with BMPR2 extracellular- or kinase-domain mutations, we were able to reproduce Activin A-driven PAH traits, including hyperproliferation, reduced apoptosis, enhanced contraction and excessive matrix production. We identified smooth muscle cell-to-myofibroblast transition as a previously unknown contributor to pulmonary vascular remodeling and demonstrate that it is blocked by sotatercept. Beyond its established effects, sotatercept rapidly reduced contractility, collagen-integrin mechanotransduction and TGF{beta} receptor expression, disrupting a pathological positive feedback loop, reflected by lower levels of circulating TGF{beta}1 in patients on sotatercept. Taken together, our patient-derived iSMC platform links mutation-dependent mechanisms of pulmonary vascular remodeling to variable drug responsiveness and reveals previously unrecognized, potentially rapid-acting modes of sotatercept in PAH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/711267v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18d5e53org.highwire.dtl.DTLVardef@2bc80dorg.highwire.dtl.DTLVardef@5ace98org.highwire.dtl.DTLVardef@1b16171_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Spatial transcriptomics uncovers hybrid, pro-inflammatory and pro-fibrotic cellular niches in pulmonary granuloma of patients with chronic sarcoidosis

BackgroundSarcoidosis is a disease of unknown etiology characterized by the formation of immune cell accumulation (granuloma) in the lung and other tissues. Chronic sarcoidosis may lead to pulmonary fibrosis. AimTo unravel cellular niches within pulmonary granuloma of chronic sarcoidosis patients using spatial transcriptomics. MethodsSpatial transcriptomics using the Visium platform (10x Genomics) was performed on nine granuloma-containing lung explants from sarcoidosis patients. Validation of gene expression was performed through immunohistofluorescence protein staining and RNA in situ hybridization. ResultsSpatial gene expression covered 30,587 gene expression spots and 173 granulomas. A CD68+ macrophage niche was localized in the center of the granuloma, with a CD3+ T and CD20+ B cell niche in close proximity, surrounded by a COL3A1+ fibroblast niche. In the central granuloma macrophage niche, expression of the pro-fibrotic macrophage genes SPP1, CHIT1 and CHI3L1 was observed, genes whose expression has recently been described for macrophages in idiopathic pulmonary fibrosis. Additionally, pro-inflammatory macrophage genes were expressed in the central granuloma niche: macrophages appear armed for lysosomal degradation and ready for phagocytosis. Inner granuloma niches showed high responsiveness to interferon gamma (IFN-{gamma}), expressing a multitude of IFN-{gamma}-induced genes. High collagen and CTHRC1 expression were observed in granuloma fibroblasts niches, characteristics of pro-fibrotic lung remodeling. Ligand-receptor analysis identified pro-inflammatory and pro-fibrotic interactions between granuloma niches. ConclusionTaken together, macrophages in the center of the sarcoidosis granuloma form an armed-and-ready, hybrid pro-inflammatory and pro-fibrotic niche, supporting granuloma persistence through continuous IFN-{gamma}-stimulation and fibrotic remodeling conducted by fibrotic fibroblasts surrounding the granuloma.

molecular biology↗

bioRxiv2024

Aberrant and Ectopic Cell Populations of the Fibrotic Pushing Border in Restrictive Allograft Syndrome after Lung Transplantation

RationaleRestrictive allograft syndrome (RAS) is a major cause of mortality in patients following lung transplantation due to rapid progressive fibrosis in the pulmonary graft. We have only limited knowledge of the cellular and molecular mechanisms that characterize the fibrosis in the RAS lung. ObjectiveTo elucidate cellularly-resolved transcriptomic and histologic characteristics of the structural cells in human RAS lungs. MethodsSingle-nuclei RNA-sequencing was performed in peripheral lung tissues from 15 RAS patients undergoing lung re-transplantation, and from 9 healthy control lungs. Findings were validated and complemented by various histologic techniques, including immunofluorescence, RNAscope, combined Elastica van Gieson-immunohistochemistry stains, and micro-CT scans. Measurement and Main resultsDifferential gene expression analysis of our single-nuclei RNA-sequencing data revealed in human RAS lungs previously undescribed and uniquely distributed aberrant basaloid cells, ectopic COL15A1+ vascular endothelial cells, and CTHRC1+ fibrotic fibroblasts, all first characterized in idiopathic pulmonary fibrosis (IPF). In contrast to IPF, RAS lacks the cellular equivalent of bronchiolization. Histologic stains confirmed our transcriptomic discoveries and disclosed distinctive distribution patterns: Aberrant basaloid cells are primarily localized at the edge of the fibrotic pushing border, forming together with the juxtaposed CTHRC1+ fibrotic fibroblasts the fibrotic niche of alveolar fibroelastosis (AFE), the histopathological hallmark in RAS lungs. On the endothelial side, PRX+ alveolar microvasculature is lost in AFE areas. Micro-CT scans revealed that blood supply, now facilitated by expanded and ectopic COL15A1+ VE cells, changes from pulmonary to systemic perfusion. Last, our data reveals potential therapeutically-modifiable expression patterns in RAS, including genes coding for the integrin subunits v{beta}6, activators of TGF{beta}. ConclusionConsidering the marked clinical, histologic and etiologic dissimilarities of RAS and IPF, our snRNAseq study revealed a surprising general principle of cellular and molecular pathogenesis in the fibrosing lung: the entity-spanning composition of the fibrotic niche by a) aberrant basaloid cells localized at the fibrotic pushing border, b) ectopic COL15A1+ vascular ECs and c) effector CTHRC1+ fibrotic fibroblasts. This general principle justifies a flexible but cellular pathogenesis-guided transferability of potential therapeutic approaches between progressive fibrotic lung diseases.

cell biology↗