Biology subjects

He, Y.-W.

Publications and source records attributed to He, Y.-W..

5 recordsLinked to original sources

bioRxiv2026

The aging modulator miR-29 is essential for adult cardiomyocyte function

Aging is the main risk factor for cardiovascular diseases, underscoring the need to identify the molecular regulators that sustain cardiac function during aging. The microRNA miR-29 is a well-established aging-associated regulator as its expression increases with age, and its overexpression promotes premature aging. Here, we define the cardiomyocyte-autonomous role of miR-29 in the adult heart by generating an inducible, cardiomyocyte-specific miR-29-deficient mouse model (Heart-iKO). We show that Heart-iKO mice develop dilated cardiomyopathy (DCM) with reduced ejection fraction that ultimately leads to premature death. Mechanistically, Heart-iKO cardiomyocytes exhibit alterations in mitochondrial structure and function. Transcriptomic profiling of bulk heart tissue and isolated cardiomyocytes revealed a consistent downregulation of genes involved in oxidative phosphorylation and the electron transport chain. We further observed a similar pattern of mitochondrial impairment in miR-29-deficient human cardiomyocytes derived from induced pluripotent stem cells (CM-iPSCs). Together, these findings highlight the context-dependent role of miR-29 in cardiac physiology and aging: although its upregulation promotes premature aging, its basal expression is required to maintain mitochondrial homeostasis and prevent heart failure in the adult myocardium.

physiology↗

bioRxiv2024

Stage-Specific Transcriptome Landscape of Hepatocellular Carcinoma: Insights from Super and Poor Survivors with Prognostic Signature Identification

BackgroundThe prognosis for hepatocellular carcinoma (HCC) patients can vary significantly even within the same clinical stage. This study aims to characterize the stage-specific transcriptomic landscape of super survivors with HCC and identify a prognostic gene signature. MethodsWe analyzed data from The Cancer Genome Atlas (TCGA) for 76 matched super survivors (alive at 5 years) and poor survivors (deceased within 1 year) with HCC. Gene set enrichment analysis stratified by stage was conducted and a key prognostic gene signature was developed. The signature was then applied to the full TCGA cohort and independently validated in International Cancer Genome Consortium (ICGC) data. FindingsStage-specific transcriptomic profiling revealed distinct patterns in super survivors. Stage I and II showed positive enrichment in immune response pathways, while stage III exhibited enhanced catabolic activities and reduced glycolysis. Across all stages, cell cycle processes were less active in super survivors. A 19-gene signature, incorporating immune, metabolic, and cell cycle genes, accurately distinguished super from poor survivors with 91% accuracy (69/76). The signature reliably predicted overall survival in both the verification cohort (1-year, 3-year, and 5-year AUROCs of 0.82, 0.80, and 0.78) and the independent validation cohort (1-year and 3-year AUROCs of 0.80 and 0.83). Consistent AUROCs were observed across all tumor stages. InterpretationOur findings reveal a dynamic shift in HCC progression, with immune dominance in early stages and metabolic dominance in later stages, alongside reduced cell cycle activity across all stages. Integrating stage-specific transcriptomic profiles offers a promising approach to enhancing individualized management for HCC patients.

bioinformatics↗

bioRxiv2024

Identification of Growth Differentiation Factor-15 as An Early Predictive Biomarker for Metabolic Dysfunction-Associated Steatohepatitis: A Nested Case-control Study of UK Biobank Proteomic Data

Background & AimsThe lack of non-invasive biomarkers for the early prediction of patients with metabolic dysfunction-associated steatohepatitis (MASH) is a major challenge for timely intervention. This study aims to determine the predictive capability for MASH long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank. MethodsA nested case-control study comprising of a MASH group and three age- and sex-matched controls groups (metabolic dysfunction-associated steatosis, viral hepatitis, and normal liver controls) were conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analyzed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years. ResultsAt baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with an AUC of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6, and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years. ConclusionGDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risk of developing MASH at a mean lag time of over 10 years.

molecular biology↗

bioRxiv2022

Mindin is essential for cutaneous fibrogenesis in a new mouse model of systemic sclerosis

Fibrosis is a result of chronically activated fibroblasts leading to the overproduction of extracellular matrix (ECM), causing tissue hardening and loss of organ function. Systemic sclerosis (SSc) is a fibrotic skin disease marked by inflammation, autoimmunity and vasculopathy along with progressive fibrosis of the skin and internal organs. A major bottleneck in understanding the etiology of SSc has been the lack of a holistic animal model that can mimic the human SSc disease. We found that the transcription factor Snail is overexpressed in the epidermis of SSc patients and a transgenic mouse recapitulating this expression pattern is sufficient to induce hallmark clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin in fibrogenesis. Mindin is produced by Snail transgenic skin keratinocytes and aids fibrogenesis by inducing inflammatory cytokine and collagen production in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

pathology↗

bioRxiv2021

Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of the matricellular protein Mindin

Intratumoral heterogeneity poses a major challenge in designing effective anti-cancer strategies. Accumulating evidence suggests that this heterogeneity arises from cancer stem cells (CSCs) that also drives tumor aggressiveness and drug resistance. The stemness of CSCs are preserved by an ill-defined combination of intrinsic and external factors and is particularly intriguing since they exist within a sea of similar cells at various degrees of differentiation. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-EMT function for the transcription factor Snail in maintaining stemness of keratinocytes. This is accomplished by the secretion of the matricellular protein Mindin from Snail expressing cells, which creates a protective niche that impedes differentiation. In an autocrine fashion, extracellular Mindin activates a Src -STAT3 pathway to reinforce the stem/progenitor phenotype and disruption of this signalling module in human cSCC attenuates tumorigenesis. The expression of Mindin in multiple carcinomas, and its critical role in cancer progression suggests that it would be a promising target for therapeutic intervention.

cell biology↗