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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature liver fibrosis is the main histological determinant of non-alcoholic steatohepatitis (NASH).
Currently, there is no effective treatment for liver fibrosis
.
Although Hippo/YAP (Yes-related protein) signaling is essential for liver regeneration, its abnormal activation often leads to fibrosis and tumorigenesis
.
Unraveling the "context-specific" contribution of YAP in liver repair may help selectively bypass fibrosis and maintain the pro-regenerative YAP function in liver disease
.
On October 11, 2021, Cao Zhongwei and Ding Yisen from Sichuan University jointly published a research paper entitled "Dopamine receptor D2 antagonization normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis" in the Journal of Hepatology (IF=25.
08).
It was found that YAP levels in macrophages increased in the livers of humans and mice with liver fibrosis
.
The fibrotic effect of macrophage YAP is by enhancing type I interferon and reducing liver fibrosis in mice
.
scRNA-Seq further showed that defects in the YAP pathway in macrophages reduced the subpopulations of fibrotic vascular endothelial cells, showing pro-fibrotic molecular features such as CTGF and VCAM1 expression
.
In order to specifically target fibrotic YAP in macrophages, the study used the GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocks macrophages instead of hepatocytes In YAP
.
The genetic and pharmacological targeting of macrophages DRD2 reduces liver fibrosis
.
In a large animal (small pig) NASH model that reproduced human pathology, DRD2 antagonists blocked fibrosis and restored liver structure
.
In summary, liver fibrosis is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), which is a disease that parallels the surge in global metabolic syndrome
.
This study shows that bone marrow-specific YAP deficiency can reduce liver fibrosis
.
Dopamine receptor D2 (DRD2) antagonism selectively blocks YAP in macrophages and prevents liver fibrosis in rodents and large animal models, showing the potential of GPCR-based NASH therapy
.
In addition, on October 6, 2021, Sichuan University Cao Zhongwei, Chen Liping and Ding Yisen jointly published a research paper entitled "Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis" in SCIENCE TRANSLATIONAL MEDICINE (IF=17.
96).
The study uses multi-omics analysis of human liver cirrhosis, Western diet and carbon tetrachloride (CCl4)-induced minipig NASH model and transgenic mice to reveal the landscape of the vascular adaptation group at the single cell level, in which endothelial cells (ECs) Together with TH17 cells cause liver cirrhosis
.
The study found that epigenetic-dependent hepatic vascular maladaptation enriched fibrotic TH17 cells to promote liver fibrosis in mice, minipigs and human patients with cirrhosis
.
Further analysis of humans, mini-pigs and mice showed that the crosstalk between histone deacetylase 2 (HDAC2) and DNA methyltransferase 1 (DNMT1) promotes maladaptation of liver endothelial cells, which promotes extracellular The production of angiosecretin IGFBP7 and ADAMTS1 in vesicles recruit fibrotic TH17 cells to the liver
.
The pharmacological targeting of HDAC2 and DNMT1 alleviated fibrosis in the minipig NASH model
.
In summary, this study shows that vascular adaptation of epigenetic reprogramming leads to liver fibrosis
.
Targeting vascular adaptation nodes may prevent maladaptive vascularization to promote liver regeneration in NASH (click to read)
.
The liver has the unique ability to regenerate damaged liver tissue
.
However, chronic or severe liver injury often leads to repair dysfunction/maladaptation and obvious scarring reactions, leading to excessive scar formation and fibrosis
.
Liver fibrosis often leads to cirrhosis and liver failure, and is also a pathological feature of non-alcoholic steatohepatitis (NASH)
.
The balance between liver regeneration and fibrosis is regulated by a "context-specific" mechanism in the liver microenvironment
.
Identifying the important cellular and molecular participants involved in this crosstalk may help bypass the pathological fibrotic response while preserving the physiological regeneration process of the damaged liver
.
Liver fibrosis involves dynamic interactions between parenchymal liver cells and non-parenchymal cells (NPC), including immune cells, hepatic stellate cells (HSC), and sinusoidal endothelial cells (EC)
.
Macrophages are important participants in regulating the process and resolution of fibrosis
.
The contribution of macrophages to liver regeneration and fibrosis has a high degree of environmental specificity.
These cells produce different cytokines and exhibit pro-fibrosis or anti-fibrosis functions during organ repair
.
After the injury begins, macrophages promote the wound healing response by promoting fibrotic factors such as transforming growth factor (TGF-β) and platelet-derived growth factor (PDGF-β)
.
When the healing response stops, macrophages release molecules such as matrix metalloproteinases (MMPs) to degrade scar tissue and promote the resolution of fibrosis
.
In addition, macrophages regulate regeneration and fibrosis by interacting with other liver cell types, including the elimination of apoptotic myofibroblasts
.
Therefore, it is described that the repair of macrophages in the liver may help stimulate liver regeneration rather than fibrosis
.
Article pattern (picture from Journal of Hepatology) Hippo/YAP pathway controls the size of animal organs by regulating cell proliferation and apoptosis, and is essential for liver cell regeneration and liver development
.
However, abnormal activation of YAP signaling is also associated with liver fibrosis and tumorigenesis
.
Selective regulation of YAP function in fibroblasts, hepatocytes and ECs can reduce liver fibrosis
.
The extensive expression and pleiotropic effects of YAP indicate that environmental or cellular compartment-specific targeting strategies can selectively inhibit its pathological functions
.
Various extracellular and intracellular signals regulate the Hippo/YAP pathway, including GPCR signaling
.
GPCR represents the largest family of membrane receptors and is a therapeutic target that is easy to treat with drugs
.
GPCR expression varies with organs and adjacent cell types, indicating that GPCR-guided therapies may be used for cell-selective pharmacological targeting of YAP
.
In this study, it was demonstrated that the fibrotic DRD2/YAP axis functions exclusively in macrophages
.
The specific deletion of Drd2 or Yap1 in macrophages induces a type I IFN response, thereby reducing the fibrotic CTGF+VCAM1+EC subset in liver fibrosis
.
High-throughput screening has produced an FDA-approved DRD2 antagonist that selectively inhibits the YAP-dependent pro-fibrotic function of macrophages
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature liver fibrosis is the main histological determinant of non-alcoholic steatohepatitis (NASH).
Currently, there is no effective treatment for liver fibrosis
.
Although Hippo/YAP (Yes-related protein) signaling is essential for liver regeneration, its abnormal activation often leads to fibrosis and tumorigenesis
.
Unraveling the "context-specific" contribution of YAP in liver repair may help selectively bypass fibrosis and maintain the pro-regenerative YAP function in liver disease
.
On October 11, 2021, Cao Zhongwei and Ding Yisen from Sichuan University jointly published a research paper entitled "Dopamine receptor D2 antagonization normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis" in the Journal of Hepatology (IF=25.
08).
It was found that YAP levels in macrophages increased in the livers of humans and mice with liver fibrosis
.
The fibrotic effect of macrophage YAP is by enhancing type I interferon and reducing liver fibrosis in mice
.
scRNA-Seq further showed that defects in the YAP pathway in macrophages reduced the subpopulations of fibrotic vascular endothelial cells, showing pro-fibrotic molecular features such as CTGF and VCAM1 expression
.
In order to specifically target fibrotic YAP in macrophages, the study used the GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocks macrophages instead of hepatocytes In YAP
.
The genetic and pharmacological targeting of macrophages DRD2 reduces liver fibrosis
.
In a large animal (small pig) NASH model that reproduced human pathology, DRD2 antagonists blocked fibrosis and restored liver structure
.
In summary, liver fibrosis is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), which is a disease that parallels the surge in global metabolic syndrome
.
This study shows that bone marrow-specific YAP deficiency can reduce liver fibrosis
.
Dopamine receptor D2 (DRD2) antagonism selectively blocks YAP in macrophages and prevents liver fibrosis in rodents and large animal models, showing the potential of GPCR-based NASH therapy
.
In addition, on October 6, 2021, Sichuan University Cao Zhongwei, Chen Liping and Ding Yisen jointly published a research paper entitled "Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis" in SCIENCE TRANSLATIONAL MEDICINE (IF=17.
96).
The study uses multi-omics analysis of human liver cirrhosis, Western diet and carbon tetrachloride (CCl4)-induced minipig NASH model and transgenic mice to reveal the landscape of the vascular adaptation group at the single cell level, in which endothelial cells (ECs) Together with TH17 cells cause liver cirrhosis
.
The study found that epigenetic-dependent hepatic vascular maladaptation enriched fibrotic TH17 cells to promote liver fibrosis in mice, minipigs and human patients with cirrhosis
.
Further analysis of humans, mini-pigs and mice showed that the crosstalk between histone deacetylase 2 (HDAC2) and DNA methyltransferase 1 (DNMT1) promotes maladaptation of liver endothelial cells, which promotes extracellular The production of angiosecretin IGFBP7 and ADAMTS1 in vesicles recruit fibrotic TH17 cells to the liver
.
The pharmacological targeting of HDAC2 and DNMT1 alleviated fibrosis in the minipig NASH model
.
In summary, this study shows that vascular adaptation of epigenetic reprogramming leads to liver fibrosis
.
Targeting vascular adaptation nodes may prevent maladaptive vascularization to promote liver regeneration in NASH (click to read)
.
The liver has the unique ability to regenerate damaged liver tissue
.
However, chronic or severe liver injury often leads to repair dysfunction/maladaptation and obvious scarring reactions, leading to excessive scar formation and fibrosis
.
Liver fibrosis often leads to cirrhosis and liver failure, and is also a pathological feature of non-alcoholic steatohepatitis (NASH)
.
The balance between liver regeneration and fibrosis is regulated by a "context-specific" mechanism in the liver microenvironment
.
Identifying the important cellular and molecular participants involved in this crosstalk may help bypass the pathological fibrotic response while preserving the physiological regeneration process of the damaged liver
.
Liver fibrosis involves dynamic interactions between parenchymal liver cells and non-parenchymal cells (NPC), including immune cells, hepatic stellate cells (HSC), and sinusoidal endothelial cells (EC)
.
Macrophages are important participants in regulating the process and resolution of fibrosis
.
The contribution of macrophages to liver regeneration and fibrosis has a high degree of environmental specificity.
These cells produce different cytokines and exhibit pro-fibrosis or anti-fibrosis functions during organ repair
.
After the injury begins, macrophages promote the wound healing response by promoting fibrotic factors such as transforming growth factor (TGF-β) and platelet-derived growth factor (PDGF-β)
.
When the healing response stops, macrophages release molecules such as matrix metalloproteinases (MMPs) to degrade scar tissue and promote the resolution of fibrosis
.
In addition, macrophages regulate regeneration and fibrosis by interacting with other liver cell types, including the elimination of apoptotic myofibroblasts
.
Therefore, it is described that the repair of macrophages in the liver may help stimulate liver regeneration rather than fibrosis
.
Article pattern (picture from Journal of Hepatology) Hippo/YAP pathway controls the size of animal organs by regulating cell proliferation and apoptosis, and is essential for liver cell regeneration and liver development
.
However, abnormal activation of YAP signaling is also associated with liver fibrosis and tumorigenesis
.
Selective regulation of YAP function in fibroblasts, hepatocytes and ECs can reduce liver fibrosis
.
The extensive expression and pleiotropic effects of YAP indicate that environmental or cellular compartment-specific targeting strategies can selectively inhibit its pathological functions
.
Various extracellular and intracellular signals regulate the Hippo/YAP pathway, including GPCR signaling
.
GPCR represents the largest family of membrane receptors and is a therapeutic target that is easy to treat with drugs
.
GPCR expression varies with organs and adjacent cell types, indicating that GPCR-guided therapies may be used for cell-selective pharmacological targeting of YAP
.
In this study, it was demonstrated that the fibrotic DRD2/YAP axis functions exclusively in macrophages
.
The specific deletion of Drd2 or Yap1 in macrophages induces a type I IFN response, thereby reducing the fibrotic CTGF+VCAM1+EC subset in liver fibrosis
.
High-throughput screening has produced an FDA-approved DRD2 antagonist that selectively inhibits the YAP-dependent pro-fibrotic function of macrophages
.
Reference message: https://
