What do megakaryocytes break down into

Related story:. Media Contact Bill Hathaway: william. More News. Albert Ko recognized for commitment, scientific approach to public health. Renovated Peabody Museum to offer free admission — forever. In fact, in vitro studies have shown that antibodies against GPIb—IX—V strongly inhibit proplatelet production and that MKs derived from patients with Bernard-Soulier syndrome do not extend proplatelets in vitro Takahashi et al.

These studies suggest that one mechanism by which GPIb—IX—V mutations cause macrothrombocytopenia in patients is through defective proplatelet formation. Fibronectin is another abundant protein in the hematopoietic microenvironment and is a proliferative stimulus for HSCs Weinstein et al.

Specifically, it plays an important role in megakaryocytopoiesis, proliferation, and differentiation through adhesion to fibronectin receptors VLA-4 very late antigen 4 and VLA-5 Han et al. Recently, the role of these receptors in proplatelet formation was examined by Matsunaga et al.

Although preliminary, these data are the first to suggest a mechanism by which fibronectin augments proplatelet formation. In sum, these studies suggest a model in which the osteoblastic niche provides an environment that allows MKs to mature and develop, whereas the vascular niche enhances proplatelet formation. In addition to functioning as the assembly lines for platelet production, the architecture and morphology of proplatelets provide a mechanism to deliver platelets to the bloodstream.

Observations of MKs releasing proplatelets in vivo have led to the notion that there is directional release of proplatelets from MKs. It is only recently, however, that studies have begun to elucidate how MKs do this.

Because of their unique position at the vascular interface, MKs are effectively exposed to a transendothelial gradient of blood components. Recently, an elegant study by Zhang et al. Once in the blood, proplatelets are exposed to a high S1P concentration, which initiates the subsequent shedding of platelets into the circulation.

Using S1pr1 knockout mice and multiphoton intravital microscopy, they showed that the S1P gradient guides proplatelet extensions into the lumen of the bone marrow sinusoids and that mice lacking S1pr1 develop severe thrombocytopenia caused by both formation of extravascular proplatelets and defective proplatelet release inside the vascular space. Therefore, this study identifies S1P and its receptor S1pr1 as important mediators of directional proplatelet elongation and terminal shedding of new platelets into the blood stream.

The implications of this study are far reaching and open the door to many interesting questions. For example, as proplatelets extend into the lumen, could they also function to monitor circulating levels of proteins, such as TPO, or even platelet numbers?

This would allow the MK to receive information and instruct the MK in processes such as protein translation, granule packaging, and platelet production.

Understanding the impact of blood components on proplatelet formation is an exciting field for future work. In another recent study, it was revealed that podosomes, cylindrical actin-rich structures found on the outer surface of the plasma membrane, actively degrade the extracellular matrix and are therefore important for MKs to extend proplatelet protrusions across the basement membrane Schachtner et al.

Once assembled, podosomes degrade matrix proteins, such as fibrinogen, in a matrix metalloproteinase- and myosin-IIA—dependent manner.

This study is the first to examine the role of podosomes in MKs and suggests that they may play a role in effective delivery of platelets into the bloodstream during proplatelet formation. Similarly, the impact of blood shear forces on proplatelet formation is an emerging trend in the field of MK and platelet biology.

In a pivotal study, Junt et al. Their observations in these live-cell experiments uphold the hypothesis that blood flow—induced shear stress helps separate proplatelet fragments from the MK cell body. This was supported by an in vitro model in which cultured MKs shed significantly more proplatelets when they were agitated compared with MKs in static cultures Junt et al. Together, these results support the idea that intravascular release of fragments protruding from mature MKs is aided by fluid shear forces in bone marrow sinusoids.

However, the majority of these studies have been performed using in vitro assays examining platelet rolling and adhesion in an open system. The development of microfluidic chips that recapitulate the bone marrow and vascular compartments will likely provide new insights into how shear influences proplatelet production and release. Once proplatelets are extended into the blood stream, what happens? Do small, platelet-sized objects or larger fragments get released into circulation?

In light of recent work, it appears that MKs release a heterogeneous mix into the blood, indicating that terminal platelet formation may continue in the blood stream. The presence of proplatelet-like structures in blood has been long recognized, and it is therefore likely that proplatelets routinely fragment from the MK body, enter the blood, and mature into platelets while in circulation.

Schwertz et al. This duplication occurs in vitro over a few hours, is dependent on an intact microtubular network, and is associated with increased protein synthesis. Subsequently, Thon et al. As in the study by Schwertz et al. The conversion from pre- to proplatelet is driven by microtubule-based forces, which are governed by two major biophysical properties: microtubule coil diameter and microtubule coil thickness Thon et al.

This supports a model in which circular preplatelets are released into the blood, rapidly and spontaneously convert into barbell proplatelets, and undergo fast rounds of abscission that result in mature platelets. Alternatively, preplatelets may become trapped in the microcapillaries of the bone marrow, lung, or spleen where intravascular shear forces drive proplatelet to platelet production. A study of higher platelet counts in postpulmonary vessels suggests that the lung may be a site of terminal platelet formation Howell and Donahue, In addition, a study using rat models reveals that lung damage may reduce circulating platelets, suggesting that the lungs play an active role in the regulation of platelet formation Xiao et al.

Platelet size correlates with platelet reactivity; larger platelets have greater prothrombotic potential. Elevated platelet size mean platelet volume is associated with increased platelet aggregation, increased expression of adhesion molecules, and elevated risk of cardiovascular and peripheral arterial diseases Bath and Butterworth, ; Kamath et al.

These observations begin to explain platelet size under normal, physiological conditions and also genetic variations that may result in macrothrombocytopenia. However, there is still much to be revealed about what regulates platelet size. A recent paper addressed this issue in a novel way; Gieger et al. From this genome-wide association study, 68 genomic loci associated with platelet volume were identified, including both previously studied and novel regulators of platelet formation.

Studies such as this pave the way for future research into genes that regulate platelet production, the results of which will be integral in understanding what molecular pathways regulate both platelet formation and size. Therefore, because of the strong effect of TPO on platelet production, clinical trials evaluating the use of recombinant TPO to treat thrombocytopenia began in Kuter and Begley, Unfortunately, some patients treated with recombinant TPO developed antibodies that created a paradoxical decrease in platelets.

This led to the creation of TPO mimetics, such as romiplostim and eltrombopag, which are highly effective in raising the platelet count in ITP Li et al. Although effective in treatment of ITP and other chronic conditions, TPO mimetics take 5 d to increase platelet counts and 12 d to reach maximum effect, making them less useful in acute situations Kuter, In addition, one serious side effect of current TPO mimetics is development of bone marrow myelofibrosis Kuter et al.

Therefore, it is obvious that other alternatives in addition to platelet transfusions are necessary to instantaneously elevate platelet counts in situations such as surgery, sepsis, trauma, or disseminated intravascular coagulation. The ability to make platelets from cultured MKs would be an extremely valuable clinical tool. Because of this, several groups have begun to create in vitro MK cultures derived from either embryonic stem cells or induced pluripotent stem cells that have the potential to create a continuous supply of platelets for infusion.

The first group to differentiate human embryonic stem cells into MKs created a co-culture system with human embryonic stem cells and stromal cells Gaur et al. In the years that followed, the field began focusing on specific ways to stimulate cell lines to become induced pluripotent stem cells. In a breakthrough study, Takahashi et al. Takayama et al. Recently, this technology was also used in dogs: canine dermal fibroblasts were used to generate canine induced pluripotent stem cells, which were then differentiated into MKs that produced functional platelets in vivo Nishimura et al.

It is clear that progress is being made at differentiating various types of cells into MKs. However, the current model is to create MKs and then collect and analyze the platelets that are released in culture, hoping that they are plentiful and functional. Because so little is known about what initiates and regulates the process of proplatelet formation, there is no direct control over the process of proplatelet and platelet formation in these systems.

As we learn more about platelet biogenesis, we may be able to create MKs that are ideal for increased proplatelet and platelet formation. Ultimately, we may be capable of generating platelets that are optimized for the job they are necessitated for, such as wound healing, immune response, or maintaining vascular integrity. In this way, platelet infusions could effectively correct pathological problems with minimal side effects.

We have made substantial progress on understanding the mechanisms that regulate thrombopoiesis and platelet formation. But, as is often the case in science, new discoveries lead to more questions.

Interestingly, the field of platelet biology is beginning to move away from thinking of platelets as just mediators of hemostasis and starting to study their role in other processes such as inflammation, immunity, and cancer.

Are there humoral regulators of proplatelet production and platelet release? In addition to revealing fundamental cellular mechanisms, future studies of platelet production will enhance our understanding of how pathological processes in the body affect platelet production and may lead to improved treatments for thrombocytopenia. We sincerely apologize to our colleagues whose work was not cited as a result of space limitations.

We would like to thank Dr. Jonathan Thon, Dr. Beth Battinelli, Dr. John Semple, and Dr. Andrew Weyrich for insightful conversations and critical review of the manuscript. Italiano Jr. Schematic of platelet production. This membrane serves as a reservoir for proplatelet formation. Transmission electron micrographs of murine MKs, preplatelets, proplatelets, and platelets. MK cultures generated from murine fetal liver cells were fixed with 1.

Images were recorded with a charge-coupled device camera 2K; Advanced Microscopy Techniques using digital acquisition and analysis software. D Detailed view of platelets bottom right and an MK, highlighting its contents.

Microtubules in proplatelets and platelets. Image acquisition was under the control of MetaMorph software Molecular Devices. A—C Images highlight the branching of proplatelets A , heterogeneous mix of platelets, pre- and proplatelets released from MKs B , and the figure 8 structure seen in preplatelet to proplatelet interconversion C.

Granules are packaged in MKs, trafficked along microtubules lining proplatelet Proplt shafts, and captured in nascent platelet tips.

MKs were then washed by albumin gradient sedimentation, and the resuspended pellet was placed in a video chamber. Image acquisition was under the control of MetaMorph software. Sign In or Create an Account. Advanced Search. User Tools. Sign In. Skip Nav Destination Article Navigation. Review June 10 The incredible journey: From megakaryocyte development to platelet formation Kellie R. Machlus , Kellie R. This Site. Google Scholar. Joseph E. Italiano, Jr. An abnormality or disease of the platelets is called a thrombocytopathy, which could be either a low number of platelets thrombocytopenia , a decrease in function of platelets thrombasthenia , or an increase in the number of platelets thrombocytosis.

In any case, issues with the number of circulating platelets is often due to issues in thrombopoietin feedback regulation, but may also be associated with genetic characteristics and certain medications and diseases. For example, thrombocytopenia often occurs in leukemia patents. Cancerous myeloid cells crowd out healthy ones in the bone marrow, causing impaired thrombopoiesis.

Privacy Policy. Skip to main content. Cardiovascular System: Blood. Search for:. Platelets Platelets, also called thrombocytes, are membrane-bound cell fragments that are essential for clot formation during wound healing. Learning Objectives Discuss the roles played by platelets in the blood. Key Takeaways Key Points Platelets, also called thrombocytes, are derived from megakaryocytes, which are derived from stem cells in the bone marrow.

Platelets circulate in the blood and are involved in hemostasis, leading to the formation of blood clots and blood coagulation. Platelets lack a nucleus, but do contain some organelles, such as mitochondria and endoplasmic reticulum fragments. If the number of platelets in the blood is too low, excessive bleeding can occur. However, if the number of platelets is too high, blood clots can form thrombosis , which may obstruct blood vessels. Platelets are a natural source of growth factors involved in wound healing, coagulatants, and inflammatory mediators.

Key Terms extracellular matrix : All the connective tissues and fibers that are not part of a cell, but rather provide support. It plays an important role in the formation of blood clots. Platelet Formation Platelets are membrane-bound cell fragments derived from megakaryocytes, which are produced during thrombopoiesis.

Learning Objectives Describe the process of platelet formation. Key Takeaways Key Points Megakaryocytes are produced from stem cells in the bone marrow by a process called thrombopoiesis. Megaryocytes create platelets by releasing protoplatelets that break up into numerous smaller, functional platelets. Thrombopoiesis is stimulated and regulated by the hormone thrombopoietin. Platelets have an average life span of five to ten days.