Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04902-z
Background Inherited cardiomyopathy (ICM) is a genetic disorder characterized by abnormal myocardial structure and function, often progressing to heart failure. FHOD3, a member of the Formin gene family, plays a crucial role in cardiomyocyte cytoskeletal organization. Mutations in FHOD3 have been associated with various cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC). However, the molecular mechanisms underlying FHOD3 deficiency-induced cardiomyopathy remain elusive. Methods A FHOD3 knockout (FHOD3-/-) human embryonic stem cell (hESC) line was generated using the CRISPR/Cas9 system and subsequently differentiated into cardiomyocytes (hESC-CMs). Sarcomere structure, calcium handling, mitochondrial function, and contractility were evaluated via immunofluorescence, electron microscopy, Seahorse metabolic analysis, and high-definition video analysis, respectively. Transcriptomic sequencing was performed to identify differentially expressed genes and enriched pathways. Results FHOD3-deficient hESC-CMs exhibited marked sarcomere disorganization and degradation, impaired calcium handling and compromised mitochondrial function, ultimately leading to reduced contractility. Transcriptomic analysis revealed significant downregulation of sarcomere-related genes and calcium-handling genes, with enrichment in pathways associated with cardiomyopathy and calcium signaling. Furthermore, FHOD3 deficiency triggered the phosphorylation of CaMKII (Thr286), a key regulator of cardiac hypertrophy and remodeling, contributing to the progression of heart failure. Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its potential as a therapeutic strategy.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04401-7
Background: Multiple sclerosis (MS) is a progressive autoimmune disease characterized by massive inflammatory infiltration, demyelination, and subsequent axonal injury and neuronal damage in the central nervous system (CNS). The etiology of MS remains unclear and there is not yet a definitive therapeutic schedule for the disease. Bone marrow mesenchymal stem cells (BMSCs), exhibiting neuroimmune-modulatory functions to alleviate various autoimmune diseases, show great potential in the treatment of MS. However, the instability of BMSCs-mediated immunosuppression in vivo has limited their application. MiR181-a, a positive regulator of immune balance, which has a preference for T cells and B cells differentiation, but degrade rapidly upon entering systemic circulation due to their unstable molecular structure. Methods: We propose a synergistic therapy approach that combines the penetrative targeting capability of BMSCs with the immuno-modulatory effects of miR181-a by overexpressing miR181-a to BMSCs through lentivirus packaging system. With this strategy, on the basis of the establishment of the experimental autoimmune encephalomyelitis (EAE) model, miR181-a overexpressing BMSCs (miR181a-BMSCs) would have a stronger immuno-modulatory treatment benefit, in terms of attenuating MS development. Results: Indicate that this method prolongs the modulatory effects of BMSCs and resulted in significantly enhancements of the proliferation of regulatory B cells (Bregs), regulatory T cells (Tregs) and the inhibition of Th17 cells compared to the traditional BMSCs group. Moreover, 10-fold miRNA’s concentration in the exosome of miR181a-BMSCs, leading to an increased duration of miRNAs to exert their biological effects. By immunotherapy and synergistic treatment, the effectiveness of the treatment is significantly enhanced, showing consistent results in different groups of the animal model.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025019
Cancer cells evade immune detection through checkpoint molecules like PD-L1 and PD-L2 which suppress T-cell activation. While PD-L1 is well-studied, the role of PD-L2 remains unclear. Pyruvate kinase M2 (PKM2), a metabolic enzyme, influences immune checkpoint regulation, but its role in PD-L1 and PD-L2 modulation is not well defined. Here, we investigate the role of pyruvate kinase M2 (PKM2) in modulating the immune checkpoint molecules PD-L1 and PD-L2 via GATA3 in cancer cells, with insights from both human and mouse models. We find that PKM2 enhances PD-L1 expression while inhibiting PD-L2, a dual regulatory mechanism that facilitates immune evasion. Knockdown and overexpression experiments revealed GATA3 as a key mediator. PKM2 knockout reduced GATA3 level, leading to decreased PD-L1 and increased PD-L2 expression. Chromatin immunoprecipitation (ChIP)-qPCR demonstrates that GATA3 functions as a direct transcription factor capable of binding to the promoters of PD-L1 and PD-L2. In silico analyses of 81 esophageal squamous cell carcinoma (ESCC) cases from the TCGA database demonstrate that PKM2 mRNA is unrelated to PD-L1 and PD-L2 expression but is negatively correlated with CD8+ T-cell infiltration in ESCC. To further validate these findings, we establish a xenograft model using immune-competent C57/BL6N mice, where knockdown of PKM2 results in significant downregulation of both PD-L1 and PD-L2 expression. Collectively, these findings underscore the divergent roles of PKM2 in regulating immune checkpoint expression in human and mouse cancer models and suggest that targeting the PKM2-GATA3 axis could enhance cancer immunotherapy by fine-tuning PD-L1 and PD-L2 levels.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024222
We aim to identify molecular clusters related to O-GlcNAcylation and establish a novel scoring system for predicting prognosis and immunotherapy efficacy in patients with gastric cancer (GC). The transcriptomic and clinical data are obtained from XENA-UCSC and GEO databases. The O-GlcNAcylation-related genes are obtained from the GSEA database. Consensus clustering analysis is employed to identify O-GlcNAcylation-related molecular clusters, and principal component analysis (PCA) is utilized to develop a novel prognostic scoring system for predicting GC outcomes and immunotherapy efficacy. The prognostic accuracy of the scoring system is assessed across five real-world cohorts. The biological function of actin alpha 2, smooth muscle (ACTA2) in GC is determined through experimental verification. Using 34 O-GlcNAcylation-related genes associated with prognosis in GC patients, these individuals are divided into two distinct subgroups characterized by different outcomes, tumor microenvironment profiles, and clinical case characteristics. The DEGs between the two subgroups are subsequently used to further divide the GC patients into two subgroups by consensus cluster analysis. PCA is used to construct a prognostic scoring system, which reveal that patients in the low-score subgroup have a better prognosis and greater benefit from immunotherapy. The accuracy of the scoring system is confirmed through validation in a cohort of patients receiving immunotherapy in the real world. ACTA2 promotes proliferation and inhibits apoptosis in GC cells. These findings suggest that we successfully establish molecular clusters associated with O-GlcNAcylation and develop a scoring system that demonstrates strong performance in predicting the prognosis of patients with GC and the effect of immunotherapy interventions.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2023275
Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL4+MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04902-z
Inherited cardiomyopathy (ICM) arises from genetic mutations that compromise myocardial structure and function, with FHOD3 mutations linked to hypertrophic, dilated, and left ventricular noncompaction cardiomyopathies. The molecular mechanisms driving FHOD3 deficiency-induced cardiomyopathy remain undefined. A FHOD3 knockout (FHOD3-/-) human embryonic stem cell line was generated via CRISPR/Cas9 and differentiated into cardiomyocytes (hESC-CMs). Sarcomere architecture, calcium handling, mitochondrial function, and contractility were assessed using immunofluorescence, electron microscopy, Seahorse metabolic analysis, and high-definition video analysis. Transcriptomic sequencing identified differentially expressed genes and enriched pathways. FHOD3-deficient hESC-CMs displayed pronounced sarcomere disorganization and degradation, impaired calcium handling, and compromised mitochondrial function, culminating in reduced contractility. Transcriptomic profiling revealed significant downregulation of sarcomere-related and calcium-handling genes, with enrichment in cardiomyopathy and calcium signaling pathways. FHOD3 deficiency triggered phosphorylation of CaMKII at Thr286, a key regulator of cardiac hypertrophy and remodeling, contributing to heart failure progression. Treatment with the myosin activator Omecamtiv mecarbil (OM) partially restored contractility without affecting calcium handling, highlighting its therapeutic potential. This human-derived loss-of-function model establishes CaMKII activation as a critical factor in FHOD3-deficiency-induced heart failure and provides a robust platform for discovering novel therapeutic agents.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025019
Cancer cells evade immune detection through checkpoint molecules PD-L1 and PD-L2, which suppress T-cell activation. While PD-L1 is well-studied, the role of PD-L2 remains unclear. Pyruvate kinase M2 (PKM2), a metabolic enzyme, influences immune checkpoint regulation, but its role in PD-L1 and PD-L2 modulation is not well defined. Here, we investigate the role of PKM2 in modulating PD-L1 and PD-L2 via GATA3 in cancer cells, with insights from both human and mouse models. We find that PKM2 enhances PD-L1 expression while inhibiting PD-L2, a dual regulatory mechanism that facilitates immune evasion. Knockdown and overexpression experiments revealed GATA3 as a key mediator. PKM2 knockout reduced GATA3 level, leading to decreased PD-L1 and increased PD-L2 expression. Chromatin immunoprecipitation (ChIP)-qPCR demonstrates that GATA3 functions as a direct transcription factor capable of binding to the promoters of PD-L1 and PD-L2. In silico analyses of 81 esophageal squamous cell carcinoma (ESCC) cases from the TCGA database demonstrate that PKM2 mRNA is unrelated to PD-L1 and PD-L2 expression but is negatively correlated with CD8+ T-cell infiltration in ESCC. To further validate these findings, we establish a xenograft model using immune-competent C57/BL6N mice, where knockdown of PKM2 results in significant downregulation of both PD-L1 and PD-L2 expression. Collectively, these findings underscore the divergent roles of PKM2 in regulating immune checkpoint expression in human and mouse cancer models and suggest that targeting the PKM2-GATA3 axis could enhance cancer immunotherapy by fine-tuning PD-L1 and PD-L2 levels.