Regulation of Platelet Production and Life Span: Role of Bcl-Xl and Potential Implications for Human Platelet Diseases
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International Journal of Molecular Sciences Review Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases Emma C. Josefsson 1,2 , William Vainchenker 3 and Chloe James 4,5,* 1 The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; [email protected] 2 Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia 3 University Paris-Saclay, INSERM UMR 1270, Gustave Roussy, 94800 Villejuif, France; [email protected] 4 University of Bordeaux, INSERM U1034, Biology of Cardiovascular Diseases, 33600 Pessac, France 5 Laboratory of Hematology, Bordeaux University Hospital Center, Haut-Leveque Hospital, 33604 Pessac, France * Correspondence: [email protected] Received: 11 September 2020; Accepted: 10 October 2020; Published: 14 October 2020 Abstract: Blood platelets have important roles in haemostasis, where they quickly stop bleeding in response to vascular damage. They have also recognised functions in thrombosis, immunity, antimicrobal defense, cancer growth and metastasis, tumour angiogenesis, lymphangiogenesis, inflammatory diseases, wound healing, liver regeneration and neurodegeneration. Their brief life span in circulation is strictly controlled by intrinsic apoptosis, where the prosurvival Bcl-2 family protein, Bcl-xL, has a major role. Blood platelets are produced by large polyploid precursor cells, megakaryocytes, residing mainly in the bone marrow. Together with Mcl-1, Bcl-xL regulates megakaryocyte survival. This review describes megakaryocyte maturation and survival, platelet production, platelet life span and diseases of abnormal platelet number with a focus on the role of Bcl-xL during these processes. Keywords: platelet; megakaryocyte; Bcl-xL 1. Platelets Platelets are small (2–4 µm in diameter), anucleate blood cells with a characteristic discoid shape. They have multiple functions and a life span of 7–10 days in human. They are produced by megakaryocytes (MKs), mostly in the bone marrow. Around 1011 platelets are produced every day. The main function of platelets is to participate in the physiological process of haemostasis, allowing bleeding to stop at the site of an injury, while maintaining normal blood flow elsewhere in the circulation. The inner surface of blood vessels is covered by endothelial cells that act as anticoagulant. After a vessel injury, the subendothelial matrix is exposed to the blood and several components of the blood will be allowed to interact with this matrix. Among these blood components are platelets. Platelets are present at 150 to 400 millions per millilitre (mL) of blood. They express receptors on their cell surface, but in a healthy blood vessel, and under normal blood flow, these receptors do not meet their ligands, and platelets do not adhere to surfaces or to each other. However, when the subendothelial matrix is exposed, the ligands for some of the platelet receptors are revealed and platelets adhere. The most important pathways in platelet adhesion is through the binding of immobilised von Willebrand factor (VWF) in the subendothelium to platelet GPIb-IX-V (CD42) and subendothelial collagen to platelet GPVI. The binding of platelet receptors with their ligands leads to platelet activation, i.e., secretion Int. J. Mol. Sci. 2020, 21, 7591; doi:10.3390/ijms21207591 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7591 2 of 12 of the content of their granules, production of thromboxane A2 and subsequent activation of other local platelets, exposure of membrane phospholipids and induction of conformational changes of the αIIbβ3 (CD41/CD61) receptors. These receptors, when activated, can bind the fibrinogen that physiologically circulates in the blood. Activated platelets will thus aggregate with each other thanks to bridges made of fibrinogen and activated αIIbβ3 receptors on the platelet surface. Within seconds, a platelet plug will be formed allowing the bleeding to stop. This process is called primary haemostasis. In parallel, another process occurs after exposure of tissue factor in the subendothelial matrix that is called coagulation. Coagulation allows formation of fibrin that will stabilise the platelet clot (for review see [1]). Platelets also have other roles than participating in haemostasis. They have been shown to be involved in immunity, antimicrobial defense [2], cancer growth and metastasis [3–5], tumour angiogenesis [6], lymphangiogenesis [5,7], inflammatory diseases [8–10], wound healing [11], liver regeneration [12] and neurodegeneration [13]. The spleen and the liver are the organs where aged platelets are destroyed, if they have not been used for haemostasis after 10 days of life. Moreover, not all platelets are circulating in the blood flow, but approximately 30% of the total platelet mass exists as an exchangeable pool residing in the spleen. This explains why increased spleen mass (splenomegaly) can be associated with lower platelet count and why absence of spleen (asplenia) is associated with increased platelet counts. 2. Regulation of Platelet Life Span by Apoptosis: Role of Bcl-xL Intrinsic apoptosis is tightly controlled by the Bcl-2 family of proteins, functionally divided into pro- and antiapoptotic proteins. Bak and Bax are the proapoptotic molecules that dictate cell fate. Activation of Bak and Bax will cause irreversible damage to the mitochondrial outer membrane with subsequent cytochrome c release, apoptosome assembly and caspase activation. In healthy cells, the antiapoptotic members Bcl-xL, Bcl-2, Mcl-1, Bcl-w, A1 and Bcl-b [14] restrain Bak and Bax. In response to cellular stress, a third group of Bcl-2 proteins, the BH3-only initiator proteins (Bim, Puma, Bad, Noxa, Bik, Hrk and Bmf), can inhibit the prosurvival proteins and indirectly as well as directly contribute to the activation of Bak and Bax [15–18]. The balance between pro- and antiapoptotic members of the intrinsic apoptosis pathway varies depending on cell type. In adults, Bcl-xL plays an essential survival function in platelets [19,20]. Platelets are a unique model in terms of life span regulation because they mostly depend on only two antagonistic Bcl-2 family members, i.e., Bcl-xL for their survival and Bak for their death [19,21], when in circulation at steady-state. However, in response to apoptotic triggers, such as pharmacological inhibition or genetic deletion of Bcl-xL, not only Bak, but both Bak and Bax regulate platelet lifespan [19,22–24]. How Bcl-xL/Bak controls platelet life span has been under intense scrutiny: in 2007, the Kile laboratory found mutations in Bcl-x that resulted in decreased platelet counts in mice due to shortened platelet life span [19]. Conversely, Bak-deficient mice exhibited a marked augmentation in platelet count due to increased platelet half-life [19,22]. Pharmacological inhibition of Bcl-xL causes thrombocytopenia in mice and humans, first demonstrated with drugs such as navitoclax (ABT-263) and ABT 737 [19,20,25]; however, in addition to Bcl-xL, they also inhibited prosurvival Bcl-2 and Bcl-w. Do other prosurvival Bcl-2 family members, in addition to Bcl-xL, contribute to the regulation of platelet life span? There is compelling evidence that both human and murine platelets express Bcl-2 protein [19,20,22,26–32]. However, as pharmacological Bcl-2 inhibition [33,34] or specific deletion in MKs and platelets [27] had no effect on platelet number and life span, Bcl-2 is unlikely to play a role in the regulation of platelet life span. While Bcl-w has been shown to be present in platelets [20,28], it is not likely to control platelet life span since systemic BCL2L2 knockout mice did not alter platelet numbers [35,36]. It is currently unclear if A1 protein is present in platelets, but A1 RNA has been detected in young human and murine platelets [37,38]. In mice, platelet counts were not changed by systemic A1a knock out [39] and another study targeting all A1 isoforms did not report any alteration of platelet counts [40]. The Mcl-1 protein has a short half-life in part as a result of fast proteosomal Int. J. Mol. Sci. 2020, 21, 7591 3 of 12 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 12 degradation. 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