Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells
Embryonic stem cells (ESCs) could potentially compensate for the lack of blood platelets available for use in transfusions. Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodie...
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| Veröffentlicht in: | The Journal of experimental medicine 2008-08, Vol.205 (8), p.1917-1927 |
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| container_title | The Journal of experimental medicine |
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| creator | Nishikii, Hidekazu Eto, Koji Tamura, Noriko Hattori, Koichi Heissig, Beate Kanaji, Taisuke Sawaguchi, Akira Goto, Shinya Ware, Jerry Nakauchi, Hiromitsu |
| description | Embryonic stem cells (ESCs) could potentially compensate for the lack of blood platelets available for use in transfusions. Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodies on day 6 demonstrated that c-Kit(+) integrin alpha IIb (alpha IIb)(+) cells, but not CD31(+) cells or vascular endothelial cadherin(+) cells, are capable of megakaryopoiesis and the release of platelet-like structures by day 12. alpha IIb beta 3-expressing ESPs exhibited ectodomain shedding of glycoprotein (GP)Ibalpha, GPV, and GPVI, but not alpha IIb beta 3 or GPIb beta. ESPs showed impaired alpha IIb beta 3 activation and integrin-mediated actin reorganization, critical events for normal platelet function. However, the administration of metalloproteinase inhibitors GM6001 or TAPI-1 during differentiation increased the expression of GPIb alpha, improving both thrombogenesis in vitro and posttransfusion recovery in vivo. Thus, the regulation of metalloproteinases in culture could be useful for obtaining high-quality, efficacious ESPs as an alternative platelet source for transfusions. |
| doi_str_mv | 10.1084/jem.20071482 |
| format | Article |
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Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodies on day 6 demonstrated that c-Kit(+) integrin alpha IIb (alpha IIb)(+) cells, but not CD31(+) cells or vascular endothelial cadherin(+) cells, are capable of megakaryopoiesis and the release of platelet-like structures by day 12. alpha IIb beta 3-expressing ESPs exhibited ectodomain shedding of glycoprotein (GP)Ibalpha, GPV, and GPVI, but not alpha IIb beta 3 or GPIb beta. ESPs showed impaired alpha IIb beta 3 activation and integrin-mediated actin reorganization, critical events for normal platelet function. However, the administration of metalloproteinase inhibitors GM6001 or TAPI-1 during differentiation increased the expression of GPIb alpha, improving both thrombogenesis in vitro and posttransfusion recovery in vivo. 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Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodies on day 6 demonstrated that c-Kit(+) integrin alpha IIb (alpha IIb)(+) cells, but not CD31(+) cells or vascular endothelial cadherin(+) cells, are capable of megakaryopoiesis and the release of platelet-like structures by day 12. alpha IIb beta 3-expressing ESPs exhibited ectodomain shedding of glycoprotein (GP)Ibalpha, GPV, and GPVI, but not alpha IIb beta 3 or GPIb beta. ESPs showed impaired alpha IIb beta 3 activation and integrin-mediated actin reorganization, critical events for normal platelet function. However, the administration of metalloproteinase inhibitors GM6001 or TAPI-1 during differentiation increased the expression of GPIb alpha, improving both thrombogenesis in vitro and posttransfusion recovery in vivo. Thus, the regulation of metalloproteinases in culture could be useful for obtaining high-quality, efficacious ESPs as an alternative platelet source for transfusions.</description><subject>Animals</subject><subject>Blood Platelets - cytology</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - enzymology</subject><subject>Cells, Cultured</subject><subject>Dipeptides - pharmacology</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Embryonic Stem Cells - drug effects</subject><subject>Embryonic Stem Cells - enzymology</subject><subject>In Vitro Techniques</subject><subject>Integrin beta3 - metabolism</subject><subject>Megakaryocytes - cytology</subject><subject>Megakaryocytes - enzymology</subject><subject>Metalloproteases - antagonists & inhibitors</subject><subject>Metalloproteases - metabolism</subject><subject>Mice</subject><subject>Platelet Glycoprotein GPIb-IX Complex - metabolism</subject><subject>Platelet Membrane Glycoprotein IIb - metabolism</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-kit - metabolism</subject><subject>Thrombopoiesis - drug effects</subject><subject>Thrombopoiesis - physiology</subject><subject>Thrombosis - etiology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkb1PHDEQxa0IFA6SLjVyRZUFjz8WbxMpQgSQQDRQW_bu7MVovb7YvpP472N0RwJVUlma9_PTvHmEfAF2CkzLsycMp5yxc5CafyALUJI1nRJ6jywY47yBqh2Qw5yfGAMpVfuRHIBuWwFcLEi6w2KnKa5SLOhnm5EmXK4nW3ycqQ91vsFM_Uw3vqRIlzhj2opxpDiOvre9j-tMV_UPTlgyHVMMNNQZUgwuPcfZ9zQXDLTHacqfyP5op4yfd-8Refxx-XBx3dzeX91cfL9tegWsNLxH2TpQ7lwJy8Qw2gHr-k4oKR04x1U7opPcCmDQWcRh6AbrZAu6aysmjsi3re9q7QIOPc4l2cmskg82PZtovXmvzP6nWcaN4YorpXk1ONkZpPhrjbmY4PNLBDtjTWfaTnQg6q3_BXKQimmQ_wMKppWu4Nct2KeYc8Lxz9rAzEvtptZuXmuv-PHbqH_hXc_iN7XbrM4</recordid><startdate>20080804</startdate><enddate>20080804</enddate><creator>Nishikii, Hidekazu</creator><creator>Eto, Koji</creator><creator>Tamura, Noriko</creator><creator>Hattori, Koichi</creator><creator>Heissig, Beate</creator><creator>Kanaji, Taisuke</creator><creator>Sawaguchi, Akira</creator><creator>Goto, Shinya</creator><creator>Ware, Jerry</creator><creator>Nakauchi, Hiromitsu</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080804</creationdate><title>Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells</title><author>Nishikii, Hidekazu ; 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| subjects | Animals Blood Platelets - cytology Blood Platelets - drug effects Blood Platelets - enzymology Cells, Cultured Dipeptides - pharmacology Embryonic Stem Cells - cytology Embryonic Stem Cells - drug effects Embryonic Stem Cells - enzymology In Vitro Techniques Integrin beta3 - metabolism Megakaryocytes - cytology Megakaryocytes - enzymology Metalloproteases - antagonists & inhibitors Metalloproteases - metabolism Mice Platelet Glycoprotein GPIb-IX Complex - metabolism Platelet Membrane Glycoprotein IIb - metabolism Protease Inhibitors - pharmacology Proto-Oncogene Proteins c-kit - metabolism Thrombopoiesis - drug effects Thrombopoiesis - physiology Thrombosis - etiology |
| title | Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells |
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