Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-7.The liver is one of the few adult tissues in mammals with the capacity for regeneration. This paper reports a surprising role for platelets in this process. Using a well-established mouse model to study liver regeneration after partial (70 percent) hepatectomy, Lesurtel et al. found that hepatocyte proliferation was dramatically diminished if the mice were rendered thrombocytopenic by either chemotherapy or immune depletion. This effect could be duplicated in mice with normal platelet counts by pharmacologic inhibition of platelet function with clopidogrel, a drug that interferes with platelet secretion by blocking the P2Y12 ADP receptor. Platelet-dependent promotion of hepatocyte regeneration was shown to result from interaction of platelet-derived serotonin (5-hydroxytryptamine) with the hepatocyte serotonin receptors 5-HT2A and 5-HT2B. Expression of these receptors increased three-to four-fold after partial hepatectomy, and their specific pharmacologic blockade produced the same effect as thrombocytopenia or clopidogrel. Furthermore, treating thrombocytopenic mice with a specific 5HT agonist restored hepatocyte proliferation after hepatectomy. The investigators also studied mice rendered null for the tryptophan-hydroxylase-1 gene. These animals lack capacity to generate peripheral 5HT and had a similar decrement in hepatocyte proliferation after resection as did thrombocytopenic mice. This was reversed by injecting 5-hydroxytryptophan to "re-load" platelets with 5HT.
Platelets play key roles in many aspects of vascular function over and above their essential and well-characterized role in primary hemostasis. An abundant literature has linked platelets to atherosclerosis, inflammation, and reperfusion injury, and recent studies have pointed to platelet involvement in angiogenesis. One of the more surprising and interesting characteristics of platelets is the large number of biologically active molecules carried in their granules — the molecules poised to be deposited at sites of vascular injury as part of the platelet release reaction. Among the repertoire of platelet α-granule constituents are peptide growth factors (e.g., PDGF and VEGF), enzymes, enzyme inhibitors, and large multifunctional glycoproteins (e.g., thrombospondin and vWF). In the dense granules are found bioactive nucleotides and amines such as ADP and 5HT. Serotonin was first isolated from blood by Irvine Page (at Cleveland Clinic) in Shortly thereafter, Marjorie Zucker and others found that nearly all serotonin in blood was associated with platelets. Platelets take up 5HT by an active transporter, and the platelet has been used as a model to study 5HT uptake, contributing greatly to our understanding of neurotransmission and the development of drugs now commonly used to treat depression and other psychiatric disorders. Serotonin functions both as a neurotransmitter and as a hormone, acting through a family of related receptors that are expressed widely but differentially. These regulate vascular tone, cardiac function, gut motility, airway reactivity, and, as shown in this report, hepatocyte proliferation. Since patients receiving liver transplantation often have portal hypertension, splenomegaly, and thrombocytopenia, this work suggests that 5HT might be a useful adjunct to promote successful transplant. These data also provide additional evidence for the concept that platelets act as targeted delivery systems for endogenous regulatory molecules. By adhering to the endothelium of injured organs and tissues and then secreting their granular contents, platelets deposit high concentrations of highly-active molecules in a regulated and localized manner. Unexpected roles for platelets in many other biological systems are likely to be discovered.
Platelets play key roles in many aspects of vascular function over and above their essential and well-characterized role in primary hemostasis. An abundant literature has linked platelets to atherosclerosis, inflammation, and reperfusion injury, and recent studies have pointed to platelet involvement in angiogenesis. One of the more surprising and interesting characteristics of platelets is the large number of biologically active molecules carried in their granules — the molecules poised to be deposited at sites of vascular injury as part of the platelet release reaction. Among the repertoire of platelet α-granule constituents are peptide growth factors (e.g., PDGF and VEGF), enzymes, enzyme inhibitors, and large multifunctional glycoproteins (e.g., thrombospondin and vWF). In the dense granules are found bioactive nucleotides and amines such as ADP and 5HT. Serotonin was first isolated from blood by Irvine Page (at Cleveland Clinic) in 1948. Shortly thereafter, Marjorie Zucker and others found that nearly all serotonin in blood was associated with platelets. Platelets take up 5HT by an active transporter, and the platelet has been used as a model to study 5HT uptake, contributing greatly to our understanding of neurotransmission and the development of drugs now commonly used to treat depression and other psychiatric disorders. Serotonin functions both as a neurotransmitter and as a hormone, acting through a family of related receptors that are expressed widely but differentially. These regulate vascular tone, cardiac function, gut motility, airway reactivity, and, as shown in this report, hepatocyte proliferation. Since patients receiving liver transplantation often have portal hypertension, splenomegaly, and thrombocytopenia, this work suggests that 5HT might be a useful adjunct to promote successful transplant. These data also provide additional evidence for the concept that platelets act as targeted delivery systems for endogenous regulatory molecules. By adhering to the endothelium of injured organs and tissues and then secreting their granular contents, platelets deposit high concentrations of highly-active molecules in a regulated and localized manner. Unexpected roles for platelets in many other biological systems are likely to be discovered.
