Biology subjects

Fallon, M.

Publications and source records attributed to Fallon, M..

5 recordsLinked to original sources

bioRxiv2026

Fibroadipogenic Progenitor Cells Contribute to Tongue Skeletal Muscle Hypertrophy in Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome (BWS) is a pediatric imprinting disorder characterized by tissue overgrowth, most commonly macroglossia, which can result in airway and feeding complications. Although dysregulated growth is a defining feature of BWS, the cellular interactions that drive organ-specific overgrowth remain poorly understood. We previously demonstrated that BWS macroglossia arises through distinct cell-intrinsic and cell-extrinsic mechanisms depending on molecular subtype. Here, we identify fibroadipogenic progenitor cells (FAPs) as modulators of myogenic differentiation and fusion in the human BWS tongue. BWS-derived FAPs were not increased in abundance in situ and did not exhibit hyperproliferation in vitro. Instead, FAPs from one BWS subtype promoted enhanced differentiation and fusion of normal human myoblasts. Secretome profiling revealed enrichment of CATHEPSIN L and TRANSFERRIN in conditioned media from these FAP populations, and functional perturbation of these factors supported their role in regulating myogenesis. These findings define a non-cell-autonomous mechanism of muscle overgrowth and implicate mesenchymal-myogenic signaling as a context-dependent driver of tissue expansion in an imprinting disorder.

cell biology↗

bioRxiv2026

Myogenic dysregulation underlies tongue overgrowth in Beckwith-Wiedemann syndrome

Macroglossia is a clinically significant feature of Beckwith-Wiedemann syndrome (BWS), but the cellular basis of tongue overgrowth remains poorly defined. Here, using pediatric tongue specimens from molecularly defined BWS subtypes and age-matched nonBWS controls, we show that BWS macroglossia is characterized by skeletal muscle fiber hypertrophy rather than increased fiber number. This phenotype is not explained by expansion or increased proliferation of satellite cells in situ, and prospectively isolated tongue satellite cells do not exhibit enhanced proliferation under growth conditions in vitro. Instead, BWS progenitors adopt distinct differentiation-associated regulatory states. IC2 loss of methylation cells sustain proliferative activity during differentiation and form enlarged myotubes, consistent with a cell-autonomous hypertrophic program. In contrast, pUPD11 cells display activation of NOTCH signaling and progenitor-associated programs, together with attenuated progression toward terminal myogenic differentiation. These findings identify skeletal muscle hypertrophy as a core tissue-level feature of BWS macroglossia and reveal that epigenetically defined BWS subtypes engage divergent myogenic programs that converge on a shared hypertrophic tissue phenotype. Together, these data define subtype-specific myogenic states in a rare human disease tissue and provide a framework for understanding how distinct epigenetic changes can produce a common overgrowth phenotype. HighlightsO_LIBWS macroglossia is associated with skeletal muscle fiber hypertrophy, not fiber hyperplasia C_LIO_LITongue satellite cell abundance and proliferation are not increased in situ in BWS C_LIO_LIIC2 loss of methylation cells sustain proliferation during differentiation and form enlarged myotubes C_LIO_LIpUPD11 cells show enhanced NOTCH signaling and a constrained myogenic state C_LI In briefTichy et al. show that Beckwith-Wiedemann syndrome macroglossia is driven by skeletal muscle hypertrophy and that distinct BWS molecular subtypes engage different myogenic regulatory programs. IC2 loss of methylation cells sustain proliferation during differentiation, whereas pUPD11 cells exhibit NOTCH-associated restraint of myogenic progression.

cell biology↗

bioRxiv2025

The Liver is an Inflammatory Mediator of Pulmonary Arterial Hypertension

The livers contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30 - 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) [≥]12, predicting higher pulmonary vascular resistance ({beta}=0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na [≥]12 had decreased 6-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.

cell biology↗

bioRxiv2023

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension

RationaleRare genetic variants and genetic variation at loci in an enhancer in SRY-Box Transcription Factor 17 (SOX17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutation in SOX17 in PAH pathogenesis has not been reported. ObjectivesTo investigate the role of SOX17 deficiency in pulmonary hypertension (PH) development. MethodsHuman lung tissue and endothelial cells (ECs) from IPAH patients were used to determine the expression of SOX17. Tie2Cre-mediated and EC-specific deletion of Sox17 mice were assessed for PH development. Single-cell RNA sequencing analysis, human lung ECs, and smooth muscle cell culture were performed to determine the role and mechanisms of SOX17 deficiency. A pharmacological approach was used in Sox17 deficiency mice for therapeutic implication. Measurement and Main ResultsSOX17 expression was downregulated in the lungs and pulmonary ECs of IPAH patients. Mice with Tie2Cre mediated Sox17 knockdown and EC-specific Sox17 deletion developed spontaneously mild PH. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced PH in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and anti-apoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction and PH development. ConclusionsOur study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.

physiology↗

bioRxiv2022

TMEM100, a Lung-Specific Endothelium Gene

The heterogeneity of endothelium across different organs was recently explored using single-cell RNA-sequencing analysis. Compared to other organs, the lung exhibits a distinct structure composed of a thin layer of capillary for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene.

physiology↗