Ontology highlight
ABSTRACT:
PROVIDER: PRJNA932946 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23423401_1.fastq.gz | Fastqsanger.gz | |||
| SRR23423401_2.fastq.gz | Fastqsanger.gz | |||
| SRR23423402_1.fastq.gz | Fastqsanger.gz | |||
| SRR23423402_2.fastq.gz | Fastqsanger.gz | |||
| SRR23423403_1.fastq.gz | Fastqsanger.gz |
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Project description:Liver fibrosis is a severe complication of diverse chronic liver diseases characterized by a dysregulated hepatic microenvironment, and effective clinical therapeutic strategies for this condition remain lacking to date. Chimeric antigen receptor macrophages (CAR-M) hold considerable therapeutic potential for liver fibrosis via antigen-specific recognition and efferocytotic activity, yet their clinical translation is largely hindered by the sophisticated ex vivo preparation procedures. Herein, we report an in situ CAR-M engineering strategy that employs a phosphatidylserine (PS)-incorporated, macrophage-targeted lipid nanoparticle (LNP) for the co-delivery of CAR mRNA and Cas9 mRNA in vivo. Our findings demonstrate that this engineered LNP achieves efficient targeting of liver-resident macrophages. Transfection with fibroblast activation protein α (FAPα)-CAR mRNA equips macrophages with the capacity to specifically target activated hepatic stellate cells (aHSCs), while Cas9-mediated follistatin-like protein 1 (FSTL-1) gene editing enhances the efferocytotic function of macrophages in liver tissues. Consequently, functional CAR-M are generated in situ, which elicits robust antifibrotic effects, including reduced collagen deposition, restored sinusoidal architecture and enhanced immune-mediated antifibrotic activity. Collectively, our customized LNP-mediated in situ engineering of liver macrophages into CAR-M enables precise antifibrotic intervention for liver fibrosis, and circumvents the cumbersome ex vivo CAR-M preparation process.
2026-08-30 | GSE327385 | GEO
Project description:To investigate the therapeutic potential of chimeric antigen receptor engineered macrophages (CAR-Ms), studies in immunocompetent mouse models are essential. However, due to the low editing efficiency and limited proliferative capacity of primary murine macrophages, efficient generation of functional CAR-Ms remains a technical challenge, hampering the advancement of this promising immunotherapeutic approach. Here, we established immortalized mouse monocytes using the DHFR-HOXB8 system, in which the presence of overexpressed HOXB8 protein is controlled by trimethoprim (TMP), allowing for conditional immortalization and subsequent macrophage differentiation. Transcriptomic and functional analyses confirmed that DHFR-HOXB8-derived cells retain bona fide monocyte and macrophage identity, closely resembling primary cells. Using this platform, we achieved CAR editing efficiencies exceeding 95% in monocytes/macrophages and showed that CAR expression conferred potent phagocytic and cytotoxic activity upon DHFR-HOXB8-derived macrophages against target cells. Adoptive transfer of FAP-targeted CAR-Ms in mouse models of myocardial infarction (MI) and transverse aortic constriction (TAC) attenuated cardiac fibrosis and improved cardiac function, demonstrating their in vivo activity and underscoring their therapeutic potential across diverse cardiac pathologies. This study thus provides a potent platform for generating genetically engineered macrophages suitable for preclinical murine studies.
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Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
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2026-03-10 | GSE300022 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
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Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
2026-03-10 | GSE300031 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
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