Letter to the Editor: Activation of lymphangiogenesis by platelets as a novel therapeutic approach for liver cirrhosis and portal hypertension

Abstract

This article offers commentary on a recent article published by Chen et al the connection between lymphangiogenesis and platelet activity - specifically, how platelets adhere, aggregate, and become activated - in a rat model of liver cirrhosis induced by bile duct ligation. Using both gain- and loss-of-function strategies, the researchers either stimulated angiogenic pathways with platelet-rich plasma or inhibited them with the vascular endothelial growth factor receptor 3 inhibitor MAZ-51. Their findings highlight the significant role that lymphangiogenesis plays in the progression of liver cirrhosis and the development of portal hypertension. Clinically, platelet transfusion has already been used to support liver function in patients with chronic liver disease and cirrhosis. Therefore, this study strengthens the rationale for using platelet therapy or targeting lymphangiogenesis pharmacologically as potential novel treatments for cirrhosis and portal hypertension.

Key Words: Liver cirrhosis; Platelet transfusion; Lymphangiogenesis; Inflammation, Portal hypertension

Core Tip: Despite encouraging findings, our understanding of how platelet transfusion enhances liver function in patients with chronic liver disease and cirrhosis remains incomplete. Unraveling the precise biological mechanisms involved could open new avenues for translating these observations into clinical practice. Moreover, to bring platelet-rich plasma-based therapies closer to routine care, clinical studies are needed to assess their safety in patients with cirrhosis. Standardizing platelet-rich plasma preparation methods and closely monitoring for potential complications, such as the risk of portal vein thrombosis, will also be essential to ensure consistent and safe clinical outcomes.

TO THE EDITOR

The development of new lymphatic vessels - known as lymphangiogenesis - is a key component of the body’s response to tissue injury[1]. These vessels play an essential role in removing immune cells, fluid, and proteins from the injured site to promote healing. Previous research has established a link between the coagulation process and lymphangiogenesis, showing that platelets contribute directly by releasing vascular endothelial growth factor (VEGF)-C, which activates the VEGFR receptor 3 (VEGFR-3) signaling pathway in lymphatic endothelial cells, thereby encouraging vessel formation[2].

In liver disease, particularly cirrhosis and portal hypertension (PHT), lymphatic dysfunction often arises due to increased vascular resistance and heightened portal vein pressure[3]. As fibrosis advances, the liver's lymphatic system adapts both structurally and functionally to help manage inflammation and reduce pressure. Enhancing lymphatic vessel formation during this process has been shown to mitigate fibrotic changes, making it a potential target for therapeutic intervention[4]. Given that cirrhosis and PHT significantly increase the risk of hepatocellular carcinoma, exploring ways to stimulate lymphangiogenesis may offer new treatment avenues[5].

We read with great interest the study by Chen et al[6] in World Journal of Gastroenterology addressed this by examining liver changes in a rat model of bile duct ligation (BDL)-induced cirrhosis using whole-transcriptome sequencing[6]. The findings revealed a strong association between platelet-related pathways and lymphatic remodeling, supporting earlier evidence that platelets can drive lymphangiogenesis and reduce fibrotic progression.

MAIN FINDINGS OF THIS STUDY

Although angiogenesis and lymphangiogenesis share overlapping molecular regulators, including VEGF family members, they represent biologically distinct processes with divergent consequences in cirrhosis. Intrahepatic angiogenesis has been shown to exacerbate PHT by increasing intrahepatic vascular resistance, whereas lymphangiogenesis may facilitate interstitial fluid clearance and inflammatory cell egress, thereby alleviating portal pressure. VEGF-C/VEGFR-3 signaling can influence both vascular compartments under certain conditions, highlighting the importance of therapeutic strategies that selectively enhance lymphatic remodeling without promoting pathological angiogenesis[7,8].

In their study, the authors first used whole-transcriptome sequencing to examine changes in the lymphatic system in a rat model of BDL. They observed a notable increase in lymphatic vessels, along with the upregulation of lymphangiogenesis-related genes, particularly VEGF-C. Building on these findings, they administered VEGF-C to further stimulate lymphatic growth, which led to a reduction in liver fibrosis.

Additionally, when they analyzed gene expression differences between BDL rats and sham-operated controls, they found that the top 30 enriched biological processes were largely associated with platelet activation and inflammation. Gene Ontology analysis further pointed to significant involvement of platelet-related components such as alpha granules, their membranes and lumens, dense granules, and pathways involved in wound repair.

To investigate the functional role of this signaling, the researchers used MAZ-51, a VEGFR-3 inhibitor, which led to a marked decrease in lymphatic vessel density and a reduction in platelet marker expression. Conversely, introducing platelet-rich plasma (PRP) into the BDL rat model improved signs of cirrhosis and portal hypertension. These improvements were linked to decreased intrahepatic angiogenesis and a dampened inflammatory response. Together, these results highlight the interplay among lymphangiogenesis, platelet activity, and liver pathology, suggesting that targeted modulation of these pathways could offer therapeutic benefits.

While the experimental data strongly support an association between platelet activation, VEGF-C signaling, and lymphatic remodeling in the BDL model, these findings should not be interpreted as establishing definitive causality.

Lymphangiogenesis in cirrhosis is regulated by a complex multicellular network involving hepatic stellate cells, macrophages, sinusoidal endothelial cells, and inflammatory mediators, many of which can independently influence portal pressure and fibrogenesis. Therefore, platelet-driven mechanisms likely represent one contributory pathway among several parallel and interacting processes[3,9].

LIMITATIONS OF THIS STUDY

This study, while insightful, does have some limitations. First, the research was conducted exclusively using a BDL rat model. Although useful, this model does not fully replicate the complex mechanisms of liver fibrosis and cirrhosis as seen in humans. To better understand the role of lymphangiogenesis in human liver disease and its potential for therapeutic targeting with platelet-based treatments, additional studies involving other experimental models and human tissue samples are needed[10].

Second, lymphangiogenesis in the liver is regulated by multiple cell types; however, this study focused only on lymphatic endothelial cells. Future investigations should explore the involvement of other key players, such as hepatic stellate cells, which are known to contribute significantly to fibrosis[11].

Another important consideration is that angiogenesis is a widespread biological process occurring throughout the body. Therapies that target angiogenic signaling pathways may carry unintended effects in other organs, raising concerns about safety and potential side effects[12]. Additionally, individual genetic differences can influence how patients respond to such therapies[13]. Future clinical studies should therefore take genetic variability into account when evaluating platelet-based or anti-angiogenic treatments for liver cirrhosis and PH.

Furthermore, platelet function is qualitatively altered in advanced cirrhosis, with abnormalities in adhesion, aggregation, and signaling that are not fully captured by platelet count alone. These functional changes raise uncertainty regarding the predictability and reproducibility of platelet-based interventions across different stages of liver disease, particularly for patients with decompensation[14].

CLINICAL SIGNIFICANCE OF THIS STUDY

Despite its limitations, this study offers valuable clinical insights. First, the authors used molecular profiling techniques to uncover a strong link between lymphangiogenesis and platelet behavior - specifically their adhesion, aggregation, and activation - in liver tissue. They further strengthened their findings by employing both activation and inhibition strategies: PRP was used to enhance angiogenic signaling, whereas MAZ-51, a VEGFR-3 inhibitor, blocked signaling. These complementary approaches in the BDL rat model helped demonstrate the critical role of lymphangiogenesis in the progression of liver cirrhosis and PHT[15].

Importantly, previous studies have shown that PRP can mitigate liver damage caused by toxic agents like carbon tetrachloride and thioacetamide, and has been effective in reducing fibrosis. Interestingly, gene expression analysis in patients with hypertrophic cardiomyopathy has also highlighted a connection between platelet activation pathways and disease progression. This suggests that platelet-driven lymphangiogenesis might extend beyond liver disease and could play a role in other pathological conditions as well[16].

Importantly, cirrhosis is now recognized as a state of “rebalanced hemostasis”, in which thrombocytopenia does not confer protection from thrombotic events. Portal vein thrombosis remains a clinically relevant complication, particularly in advanced disease. Prior pharmacologic attempts to increase platelet count or activity in chronic liver disease most notably with thrombopoietin receptor agonists such as eltrombopag have been associated with an increased incidence of portal venous thrombotic events. These observations underscore the need for caution when extrapolating platelet-based therapeutic strategies to patients with decompensated cirrhosis[17,18].

THERAPEUTIC OPPURTUNITIES BEYOND THE ORIGINAL STUDY

Recent findings have highlighted the therapeutic potential of platelet-derived products in liver disease. One study demonstrated that extracellular vesicles isolated from PRP were effective in improving liver cirrhosis in a mouse model[19]. Clinically, platelet transfusions have already been used to support liver function in patients with chronic liver disease and cirrhosis[20]. On another front, the anti-angiogenic medication regorafenib has shown promise in reducing PH by targeting and limiting liver fibrosis[21].

Although the VEGF-C/VEGFR-3 signaling pathway is widely recognized as the central regulator of lymphangiogenesis, emerging research suggests that several other molecular pathways also play important roles. These alternative mechanisms present new opportunities for therapeutic development[22]. Together, the accumulating evidence points toward platelet-based therapies and targeted modulation of lymphangiogenesis as promising novel strategies for treating liver cirrhosis and PHT.

In addition to VEGF-C, platelet-derived products contain a broad spectrum of bioactive mediators, including platelet-derived growth factor, transforming growth factor beta, and VEGF-A family members. In the cirrhotic liver, these factors may exert context-dependent pro-fibrotic or pro-angiogenic effects by promoting hepatic stellate cell activation, pathological angiogenesis, and endothelial dysfunction. Such off-target actions are particularly relevant given the already dysregulated vascular and fibrotic milieu in advanced cirrhosis and warrant careful evaluation in future translational studies[23,24].

CONCLUSION

Despite encouraging findings, our understanding of how platelet transfusion enhances liver function in patients with chronic liver disease and cirrhosis remains incomplete. Unraveling the precise biological mechanisms involved could open new avenues for translating these observations into clinical practice. Moreover, to bring PRP-based therapies closer to routine care, clinical studies are needed to assess their safety in cirrhotic patients. Standardizing PRP preparation methods and closely monitoring for potential complications such as the risk of portal vein thrombosis will also be essential to ensure consistent and safe clinical outcomes. Taken together, platelet-driven lymphangiogenesis represents a compelling and biologically plausible therapeutic concept; however, its translation into clinical practice will require rigorous evaluation of thrombotic risk, off-target vascular and fibrogenic effects, and disease-stage-specific platelet dysfunction. Such considerations are particularly critical in patients with decompensated cirrhosis, in whom the hemostatic and vascular balance is especially fragile.