Clinical evidence for thrombospondin-1 as a relevant suppressor of liver regeneration

Starlinger, Patrick; Schauer, Dominic; Alidzanovic, Lejla; Zikeli, Silvia; Gebhardt, Kristina; Luf, Florian; Fleischmann, Edith; Perisanidis, Beata; Gruenberger, Birgit; Gruenberger, Thomas; Brostjan, Christine

doi:10.1016/j.jhep.2012.11.037

Cited by 18 publications

(19 citation statements)

References 8 publications

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“…Accordingly, theoretically one could suggest that platelets suppress rather than promote liver regeneration. Of note, we were able to provide extensive clinical evidence that increased circulating TSP-1 on the first postoperative day after liver resection was highly predictive for postoperative liver dysfunction [5,15,16], indicating that platelets represent a double-edged sword in liver regeneration.…”

Section: How Do Platelets Modulate Liver Regeneration?mentioning

confidence: 77%

Importance of platelet-derived growth factors in liver regeneration

Starlinger

Assinger

2016

Expert Review of Gastroenterology & Hepatology

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Section: How Do Platelets Modulate Liver Regeneration?mentioning

confidence: 77%

Importance of platelet-derived growth factors in liver regeneration

Starlinger

Assinger

2016

Expert Review of Gastroenterology & Hepatology

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“…Whereas VEGF is proregenerative, TSP‐1 has negative effects on LR . Of note, it has been proposed that pro‐ and antiangiogenic proteins are organized into separate platelet α‐granules and are differentially released upon activation .…”

Section: Discussionmentioning

confidence: 99%

“…Whereas VEGF is proregenerative, TSP-1 has negative effects on LR. (10,26) Of note, it has been proposed that pro-and antiangiogenic proteins are organized into separate platelet a-granules and are differentially released upon activation. (4) In vitro data revealed that different a-granule subsets are selectively released by specific agonists, as suggested by agonist-specific a-granule secretion kinetics.…”

Section: Discussionmentioning

confidence: 99%

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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“…Further, recent evidence has shown that interactions between platelets and endothelial cells are important in wound healing and could potentially play a significant role in liver regeneration . In humans, platelet α ‐granule release profiles and plasma levels of vascular endothelial growth factor and thrombospondin‐1 were predictive of liver dysfunction after partial hepatectomy .…”

Section: Platelets Stimulate Hepatocyte Proliferation Through Interacmentioning

confidence: 99%

Platelets in liver regeneration

Meyer

Balaphas

Fontana

et al. 2017

ISBT Science Series

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Background and Objectives Loss of liver tissue leading to impairment of liver function represents a major cause of mortality. Understanding the mechanism of liver regeneration and developing therapies to sustain liver regeneration are of high therapeutic relevance. In this regard, platelets are considered as potential candidates for stimulating liver regeneration.Methods We aim to review the most recent evidence regarding the role of platelets in liver regeneration.Results Platelets stimulate liver regeneration in animal models of liver resection. In humans, platelets are independent predictors of postoperative mortality, liver function and volume recovery. One proposed mechanism by which platelets stimulate liver regeneration relies on their direct effect on hepatocytes. Following partial hepatectomy, platelets accumulate in the residual liver and release their granule content. Platelet-containing molecules, such as HGF, VEGF, IGF-1 and serotonin, stimulate hepatocyte proliferation. A putative additional mechanism involves the transfer of platelet mRNA to hepatocytes following platelet internalization. Recent studies have suggested that the effect of platelets relies on their interactions with LSEC. Platelets induce the secretion of IL-6 from LSEC, a strong initiator of hepatocyte proliferation. Additionally, platelets convey molecules that may impact LSEC function and, by extension, liver regeneration. Platelets potentially interact with Kupffer cells, but the effect of that interaction on liver regeneration remains to be determined.Conclusion Platelets stimulate liver regeneration. Several mechanisms seem to be involved, acting on the level of hepatocytes, LSEC and potentially Kupffer cells. Identification of the platelet-molecule(s) involved may lead to targeted therapies for patients with impairment of liver function.

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Clinical evidence for thrombospondin-1 as a relevant suppressor of liver regeneration

Cited by 18 publications

References 8 publications

Importance of platelet-derived growth factors in liver regeneration

Importance of platelet-derived growth factors in liver regeneration

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

Platelets in liver regeneration

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