A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process?

Meyer, Jérémy; Lejmi, Esma; Fontana, Pierre; Morel, Philippe; Gonelle‐Gispert, Carmen; Bühler, Léo H.

doi:10.1016/j.jhep.2015.07.002

Cited by 81 publications

(84 citation statements)

References 96 publications

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“…Accordingly, endothelial cell dysfunction itself could contribute to specific α‐granule release, which, in turn, affects LR. Of note, platelets can directly interact with LSECs and thereby modify hepatocyte proliferation, as recently reviewed by Meyer et al…”

Section: Discussionmentioning

confidence: 98%

The profile of platelet α‐granule released molecules affects postoperative liver regeneration

et al. 2015

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Platelets promote liver regeneration through site-specific serotonin release from dense granules, triggering proliferative signaling in hepatocytes. However, the effects of factors derived from platelet a-granules on liver regeneration are unclear, because a-granules contain bioactive molecules with opposing functions. Because a-granule molecules are stored in separate compartments, it has been suggested that platelets selectively release their a-granule content dependent on the environmental stimulus. Therefore, we investigated the pattern of circulating a-granule molecules during liver regeneration in 157 patients undergoing partial hepatectomy. We measured plasma levels of a-granule-derived factors in the liver vein at the end of liver resection, as well as on the first postoperative day. We observed a rapid accumulation of platelets within the liver after induction of liver regeneration. Platelet count and P-selectin (a ubiquitous cargo of a-granules) were not associated with postoperative liver dysfunction. However, low plasma levels of vascular endothelial growth factor (VEGF), but high levels of thrombospondin 1 (TSP-1), predicted liver dysfunction after resection. Patients with an unfavorable postoperative a-granule release profile (high TSP-1/low VEGF) showed substantially worse postoperative clinical outcomes. The unfavorable postoperative a-granule release profile was associated with increased postoperative portal venous pressure and von Willebrand factor antigen levels as a marker for intrahepatic endothelial dysfunction. Conclusion: The postoperative profile of circulating platelet-derived factors correlates with the ability of the remnant liver to regenerate. Portal venous pressure and intrahepatic endothelial dysfunction might account for the selective granule release profile. Selective modulation of platelet a-granule release in patients may represent an attractive target for therapeutic interventions to improve liver regeneration and clinical outcomes after partial hepatectomy. (HEPATOLOGY 2016;63:1675-1688 P latelets are critically involved not only in hemostasis, but also in inflammation, wound healing and angiogenesis. Through release of their granule content, they orchestrate signal responses in a plethora of target cells, including hepatocytes. Platelets are potent inducers of liver regeneration (LR) after partial hepatectomy and platelet activation as well as granule release increase after liver resection.(1,2) Platelet activation results in the release of dense granules, followed by secretion of a-granule content.(3) Exocytosis of a-granules represents a highly regulated process, involving distinct packaging

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Section: Discussionmentioning

confidence: 98%

The profile of platelet α‐granule released molecules affects postoperative liver regeneration

et al. 2015

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“…However, the role of both mechanisms, i.e . the release of growth factors and/or RNA transfer from platelets, in liver regeneration needs confirmation in vivo [79,80]. …”

Section: Liver Fibrosis and Plateletsmentioning

confidence: 99%

Platelets in liver disease, cancer and regeneration

Kurokawa

Ohkohchi

2017

WJG

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Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.

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“…There is an increasing body of evidence to suggest that platelets support liver regeneration upon partial hepatectomy and chronic/acute liver injury . Meyer et al .…”

Section: The Role Of Platelet Clec‐2 In Tissue Regenerationmentioning

confidence: 99%

Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood

Suzuki‐Inoue

Osada

Ozaki

2017

Journal of Thrombosis and Haemostasis

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Summary A platelet activation receptor, C‐type lectin‐like receptor 2 (CLEC‐2), has been identified as a receptor for a platelet‐activating snake venom, rhodocytin. CLEC‐2 protein is highly expressed in platelets/megakaryocytes, and at lower levels in liver Kupffer cells. Recently, podoplanin has been revealed as an endogenous ligand for CLEC‐2. Podoplanin is expressed in certain types of tumor cells, fibroblastic reticular cells (FRCs) in lymph nodes, kidney podocytes, and lymphatic endothelial cells, but not in vascular endothelial cells. CLEC‐2 in platelets cannot have access to podoplanin under normal conditions, but they interact with each other under pathologic conditions or during developmental stages, and play various pathophysiologic roles. CLEC‐2 facilitates hematogenous metastasis of podoplanin‐expressing tumors. During development, the interaction between CLEC‐2 and podoplanin in lymphatic endothelial cells or neuroepithelial cells facilitates blood–lymphatic vessel separation and cerebrovascular patterning and integrity, respectively. In adulthood, platelet CLEC‐2 binding to FRCs is crucial for maintenance of the integrity of high endothelial venules in lymph nodes. Podoplanin‐expressing FRC‐like cells have recently been identified in the bone marrow, and facilitate megakaryocyte proliferation and proplatelet formation by binding to megakaryocyte CLEC‐2. Podoplanin is inducibly expressed in liver monocytes and keratinocytes during Salmonella infection and wound healing, and regulates thrombus formation in the liver and controlled wound healing, respectively. By binding to unknown ligands, platelet CLEC‐2 regulates the maintenance of vascular integrity during inflammation, thrombus stability under flow, and maintenance of quiescence of hematopoietic stem cells. Podoplanin is expressed in various cells, and additional roles of the CLEC‐2–podoplanin interaction will be revealed in the future.

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A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process?

Cited by 81 publications

References 96 publications

The profile of platelet α‐granule released molecules affects postoperative liver regeneration

The profile of platelet α‐granule released molecules affects postoperative liver regeneration

Platelets in liver disease, cancer and regeneration

Physiologic and pathophysiologic roles of interaction between C‐type lectin‐like receptor 2 and podoplanin: partners from in utero to adulthood

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