Abstract
Thrombocytopoiesis is a complex process beginning at the level of hematopoietic stem cells, which ultimately generate megakaryocytes, large marrow cells with a distinctive morphology, and then, through a process of terminal maturation, megakaryocytes shed thousands of platelets into the circulation. This process is controlled by intrinsic and extrinsic factors. Emerging data indicate that an important intrinsic control on the late stages of thrombopoiesis is exerted by integrins, a family of transmembrane receptors composed of one α and one β subunit. One β subunit expressed by megakaryocytes is the β1 integrin, the role of which in the regulation of platelet formation is beginning to be clarified. Here, we review recent data indicating that activation of β1 integrin by outside-in and inside-out signaling regulates the interaction of megakaryocytes with the endosteal niche, which triggers their maturation, while its inactivation by galactosylation determines the migration of these cells to the perivascular niche, where they complete their terminal maturation and release platelets in the bloodstream. Furthermore, β1 integrin mediates the activation of transforming growth factor β (TGF-β), a protein produced by megakaryocytes that may act in an autocrine fashion to halt their maturation and affect the composition of their surrounding extracellular matrix. These findings suggest that β1 integrin could be a therapeutic target for inherited and acquired disorders of platelet production.
Highlights
Megakaryocytes (MKs) are large cells produced in the bone marrow that undergo a process of terminal maturation to produce platelets, which are blood cells critical for vascular integrity and the trigger of the coagulation process
MKs are produced in the endosteal niche of the bone marrow through a process termed megakaryocytopoiesis, which begins with the hematopoietic stem cells (HSCs) and involves the generation of progenitor cells progressively more committed toward the MK lineage (Figure 1)
For example, that the podocytes of the rat glomeruli respond to TGF-β1 by activating a MAPK signaling that regulates the ratio of β1 and β3 integrin expressed by these cells, altering their adhesion and migration properties[78,79]
Summary
Megakaryocytes (MKs) are large cells produced in the bone marrow that undergo a process of terminal maturation to produce platelets, which are blood cells critical for vascular integrity and the trigger of the coagulation process. For example, that the podocytes of the rat glomeruli respond to TGF-β1 by activating a MAPK signaling that regulates the ratio of β1 and β3 integrin expressed by these cells, altering their adhesion and migration properties[78,79] Whether this regulatory feedback loop operates in MKs has not yet been established. It is well established that increased expression of TGF-β in the microenvironment may induce fibrosis by activating the fibroblasts to secrete collagen[98] and by increasing the levels of lysyl-oxidase released by the MKs necessary for its polymerization[118] This knowledge has suggested the therapeutic hypothesis, currently under clinical investigation, that myelofibrosis can be treated by the TGF-β1–specific trap AVID200 (NCT03895112119)[120]. The role played by β1 integrin on TGF-β activation discussed above suggests that drugs targeting this integrin subunit are potentially effective in treating myelofibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
