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Italiano, Joseph

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Italiano

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Joseph

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Italiano, Joseph
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    The incredible journey: From megakaryocyte development to platelet formation
    (The Rockefeller University Press, 2013) Machlus, Kellie; Italiano, Joseph
    Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications.
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    Scalable Generation of Universal Platelets from Human Induced Pluripotent Stem Cells
    (Elsevier, 2014) Feng, Qiang; Shabrani, Namrata; Thon, Jonathan N.; Huo, Hongguang; Thiel, Austin; Machlus, Kellie R.; Kim, Kyungho; Brooks, Julie; Li, Feng; Luo, Chenmei; Kimbrel, Erin A.; Wang, Jiwu; Kim, Kwang-Soo; Italiano, Joseph; Cho, Jaehyung; Lu, Shi-Jiang; Lanza, Robert
    Summary Human induced pluripotent stem cells (iPSCs) provide a potentially replenishable source for the production of transfusable platelets. Here, we describe a method to generate megakaryocytes (MKs) and functional platelets from iPSCs in a scalable manner under serum/feeder-free conditions. The method also permits the cryopreservation of MK progenitors, enabling a rapid “surge” capacity when large numbers of platelets are needed. Ultrastructural/morphological analyses show no major differences between iPSC platelets and human blood platelets. iPSC platelets form aggregates, lamellipodia, and filopodia after activation and circulate in macrophage-depleted animals and incorporate into developing mouse thrombi in a manner identical to human platelets. By knocking out the β2-microglobulin gene, we have generated platelets that are negative for the major histocompatibility antigens. The scalable generation of HLA-ABC-negative platelets from a renewable cell source represents an important step toward generating universal platelets for transfusion as well as a potential strategy for the management of platelet refractoriness.
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    IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs
    (The Rockefeller University Press, 2015) Nishimura, Satoshi; Nagasaki, Mika; Kunishima, Shinji; Sawaguchi, Akira; Sakata, Asuka; Sakaguchi, Hiroyasu; Ohmori, Tsukasa; Manabe, Ichiro; Italiano, Joseph; Ryu, Tomiko; Takayama, Naoya; Komuro, Issei; Kadowaki, Takashi; Eto, Koji; Nagai, Ryozo
    Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture–dependent thrombopoiesis and increased platelet counts. IL-1α–IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.
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    Platelets Generated from Human Embryonic Stem Cells are Functional In Vitro and in the Microcirculation of Living Mice
    (Nature Publishing Group, 2011) Lu, Shi-Jiang; Li, Feng; Feng, Qiang; Kimbrel, Erin A; Hahm, Eunsil; Cho, Jaehyung; Lanza, Robert; Yin, Hong; Thon, Jonathan; Wang, Wei; Italiano, Joseph
    Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scale. Differential-interference contrast and electron microscopy analyses showed that ultrastructural and morphological features of hESC-derived platelets were indistinguishable from those of normal blood platelets. In functional assays, hESC-derived platelets responded to thrombin stimulation, formed microaggregates, and facilitated clot formation/retraction in vitro. Live cell microscopy demonstrated that hESC-platelets formed lamellipodia and filopodia in response to thrombin activation, and tethered to each other as observed in normal blood. Using real-time intravital imaging with high-speed video microscopy, we have also shown that hESC-derived platelets contribute to developing thrombi at sites of laser-induced vascular injury in mice, providing the first evidence for in vivo functionality of hESC-derived platelets. These results represent an important step toward generating an unlimited supply of platelets for transfusion. Since platelets contain no genetic material, they are ideal candidates for early clinical translation involving human pluripotent stem cells.
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    T granules in human platelets function in TLR9 organization and signaling
    (The Rockefeller University Press, 2012) Thon, Jonathan; Peters, Christopher G.; Machlus, Kellie; Aslam, Rukhsana; Rowley, Jesse; Macleod, Hannah; Devine, Matthew T.; Fuchs, Tobias A; Weyrich, Andrew S.; Semple, John W.; Flaumenhaft, Robert; Italiano, Joseph
    Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxynucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs.
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    Cytoskeletal Mechanics of Proplatelet Maturation and Platelet Release
    (Rockefeller University Press, 2010) Thon, Jonathan; Montalvo, Alejandro; Patel-Hett, Sunita; Devine, Matthew T.; Richardson, Jennifer L.; Ehrlicher, Allen Joseph; Larson, Mark K.; Hoffmeister, Karin; Hartwig, John; Italiano, Joseph
    Megakaryocytes generate platelets by remodeling their cytoplasm into long proplatelet extensions, which serve as assembly lines for platelet production. Although the mechanics of proplatelet elongation have been studied, the terminal steps of proplatelet maturation and platelet release remain poorly understood. To elucidate this process, released proplatelets were isolated, and their conversion into individual platelets was assessed. This enabled us to (a) define and quantify the different stages in platelet maturation, (b) identify a new intermediate stage in platelet production, the preplatelet, (c) delineate the cytoskeletal mechanics involved in preplatelet/proplatelet interconversion, and (d) model proplatelet fission and platelet release. Preplatelets are anucleate discoid particles 2–10 \(\mu\)m across that have the capacity to convert reversibly into elongated proplatelets by twisting microtubule-based forces that can be visualized in proplatelets expressing GFP–\(\beta\)1-tubulin. The release of platelets from the ends of proplatelets occurs at an increasing rate in time during culture, as larger proplatelets undergo successive fission, and is potentiated by shear.