Biology subjects

gao, l.

Publications and source records attributed to gao, l..

4 recordsLinked to original sources

bioRxiv2026

Therapeutic Potential of Hypoxia-Preconditioned hiPSC-Epicardial Cell-Derived Exosomes in Mice with Myocardial Infarction

BackgroundIt has been demonstrated that stem cell transplantation promotes healing of the infarcted heart through paracrine effects. However, the therapeutic potential of exosomes secreted by hiPSC-derived epicardial cells (hEP-Exos) for treating infarcted hearts remains unclear. Myocardial infarction (MI) can trigger EP activation, increasing EP paracrine function. Therefore, this study aims to determine and compare the cardioprotective effects of exosomes secreted by hEPs under normoxic (Exo-N) and hypoxic (Exo-H) conditions in MI mice and to explore the underlying mechanisms. MethodsTwo types of exosomes were collected by ultracentrifugation and delivered via intramyocardial injection in a murine MI model. The protective effects of Exo-N and Exo-H on the infarcted heart were assessed using echocardiography, histological examination, and immunofluorescence analysis. Additionally, microRNA sequencing, luciferase activity assays, and miRNA gain-and loss-of-function experiments were performed to identify enriched miRNAs and investigate their roles in different exosome populations. ResultsIn vitro, both Exo-N and Exo-H enhanced the migration and tube-formation capacities in human umbilical vein endothelial cells (HUVECs) and reduced the apoptosis in hiPSC-derived cardiomyocytes (hCMs) under oxygen-glucose deprivation (OGD), with Exo-H exhibiting a stronger effect. In vivo, both Exo-N and Exo-H significantly improved contractile function, reduced infarct size, and mitigated adverse remodeling in mouse hearts with MI, accompanied by increased cardiomyocyte survival and angiogenesis, with Exo-H showing superior efficacy. Mechanistically, miRNA sequencing revealed distinct cargo profiles between Exo-N and Exo-H. miR-214-3p was identified as a key mediator of the enhanced therapeutic potency of Exo-H. miR-214-3p promoted EC angiogenesis by suppressing vasohibin-1 and attenuated cardiomyocyte mitochondrial fission and apoptosis by suppressing mitochondrial elongation factor 2 (MIEF2). ConclusionsThis study demonstrates that administration of hEP-Exos, particularly Exo-H, provides robust cardioprotection by enhancing cardiomyocyte survival and angiogenesis, potentially mediated by miR-214-3p. These findings suggest that conditioned hEP-Exos could be a promising and effective acellular therapeutic option for treating MI.

cell biology↗

bioRxiv2026

TRPC6 channel inhibition disturbs store-operated Ca2+ entry to delay proliferation in bladder cancer

Background and ObjectiveDespite its prevalence, bladder cancer (BC) remains an unsolved pathogenesis. It is believed that TRPC6 channels have unique electrophysiological properties that contribute to intracellular Ca2+ signalling and tumorigenesis in cells. However, the mechanism by which TRPC6 contributes to BC progression and intracellular Ca2+ homeostasis remains unclear. MethodIn this study, TRPC6 expressions in paired BC and adjacent normal tissues were measured by immunohistochemistry. A KEGG pathway enrichment analysis was conducted to determine TRPC6s potential contribution to BC. Ca2+ imaging analysis was performed to explore the contribution of TRPC6 in the BC cell. Flow cytometry and Cell Counting Kit-8 assay were performed to explore the effects of TRPC6 on the proliferation of BC. The impacts of TRPC6 SOCE on PI3K/Akt/mTOR pathway were measured by western blot. Based on the above bunch of studies, TRPC6 was found to be overexpressed in human BC tissue, which correlated with poor survival rates for patient overall survival (OS). We used the TRPC6-specific antagonist SAR7334 to explore and reveal significant inhibition of BC cell proliferation. Mechanistically, TRPC6 mediated cytosolic Ca2+ and regulation of SOCE, leading to the activation of the IP3K/AKT/mTOR pathway. ResultsWe found that SAR7334 arrested the phosphorylation of PI3K and Akt, thus causing a significant decrease in phosphorylated mTOR. Similar effects were observed for the SOCE-specific antagonist MRS1845. In contrast, the Akt inhibitor MK2206 did not alter the SOCE in BC cells. Conclusionsour results indicate that the pharmacological inhibition of TRPC6 arrests tumour cell proliferation through SOCE targeting the PI3K/Akt/mTOR pathway. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/702689v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@bf783aorg.highwire.dtl.DTLVardef@6e3487org.highwire.dtl.DTLVardef@13aad23org.highwire.dtl.DTLVardef@13cfe7e_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic of proposed pathway. A model for summarizing TRPC6 contributes to cell proliferation in bladder cancer. TRPC6 specific inhibitor SAR7334 alter cellular cytosolic Ca2+ and SOCE, thus arrested phosphorylation of the PI3K/Akt pathway and the proliferation of bladder cancer cells.

cancer biology↗

bioRxiv2019

An atlas of infiltrated B-lymphocytes in breast cancer revealed by paired single-cell RNA-sequencing and antigen receptor profiling

While it has been well-recognized that T-cell mediated adaptive cellular immunity plays important roles in cancer immune response and tumor control, the roles of B lymphocytes in tumor development and therapy have only been proposed until recently, and are still mostly controversial. To gain mechanistic insights into the origin and dynamics of tumor infiltrated immune cells, especially B lymphocytes, we combine single-cell RNA-sequencing and antigen receptor lineage analysis to characterize a large number of triple-negative breast cancer (TNBC) infiltrated immune cells and present a comprehensive atlas of infiltrated B-lymphocytes in TNBC, the most aggressive breast cancer subtype. We demonstrate that TNBC infiltrated B cells showed more mature and memory B cell characteristics, as well as high clonality and extensive IgH class switching recombination and somatic hypermutations. The B cell signatures based on single-cell RNA-seq results are significantly associated with improved survival for TNBC patients and provide better prognostication than classic single B cell markers (CD19 or CD20). Further dissection of the mechanisms regulating the functions and dynamic distribution of tumor infiltrated B cell populations will provide new clues for tumor immunotherapy.

immunology↗

bioRxiv2019

Respiratory syncytial virus activates Rab5a to suppress IRF1-dependent IFN-{lambda} production, subverting the antiviral defense of airway epithelial cells

Human respiratory syncytial virus (RSV) is a negative-strand RNA virus that causes severe acute pediatric respiratory tract infections worldwide. The limited effective antiviral options and lack of an effective vaccine against RSV highlight the need for a novel anti-viral therapy. One alternative is to identify and target the host factors required for viral infection. All viruses, including RSV, utilize cellular trafficking machinery to fulfill their life cycle in the infected host cells. Rab proteins mediate specific steps in intracellular membrane trafficking through the recruitment and tethering of fusion factors, and docking with actin- or microtubule-based motor proteins. Using RNA interference to knock down Rab proteins, we document that the micropinocytosis-associated Rab5a is required for RSV infection. RSV infection itself induces activation of Rab5a, and inhibition of this activation reduces RSV infection, but the mechanism for this effect remains unknown. Interferon (IFN) signaling plays an important role in innate immunity, and recent studies have identified IFN-{lambda} (lambda), a type III IFN, as the most important IFN for antiviral immune in response to RSV infection of mucosal epithelium. However, how the RSV-induced Rab5a suppresses airway epithelial antiviral immunity has not been unraveled. Here, we show that activated Rab5a inhibits IRF1-induced IFN-{lambda} production and IFN-{lambda}-mediated signal transduction via JAK-STAT1, thereby increasing viral replication. Rab5a knockdown by siRNA resulted in stimulation of IRF1, IFN-{lambda} and JAK-STAT1 expression, and suppressed viral growth. Our results highlight new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection. Author summaryRSV is the leading cause of lower respiratory tract infection in under 5 years old children. Worldwide. We identified Rab5a as a host factor involved in RSV infection via RNA interference to knock down familiar Rab proteins in human lung epithelial A549 cells infected with RSV. Rab5a belongs to Rab GTPases subfamily, which contributes to intracellular trafficking to promote virus infection. Knockdown or inactive (GDP-bound) Rab5a results in low infection and replication through stimulating IRF1, IFN-{lambda} and JAK-STAT1 expression, and suppressed viral growth. Besides, we propose that the regulation of Rab5a expression during RSV infection might be a viral strategy to promote its infectivity.

immunology↗