Abstract
Platelet transfusion is required for life-threatening thrombocytopenic bleeding, and single donor platelet concentrate is the ideal transfusion product. However, due to the inadequate number of donors that can donate a large volume of platelets, in vitro platelets production could be an alternative. We developed an in vitro production system designed to increase the platelet production yield from cultured cells. Previously, we reported that depletion of a Hippo pathway core kinase (LATS1/2) inhibited platelet production from cultured megakaryocytes. In the present study, we further investigated the role of the Hippo pathway in megakaryocyte proliferation and platelet production by focusing on the role of its effector proteins (YAP and TAZ), which are down-stream targets of LATS1/2 kinase. We found that YAP plays an essential role in megakaryoblastic cell proliferation, maturation, and platelet production, while TAZ showed minor effect. Knockdown of YAP, either by genetic manipulation or pharmaceutical molecule, significantly increased caspase-3-mediated apoptosis in cultured megakaryocytes, and increased platelet production as opposed to overexpressing YAP. We, therefore, demonstrate a paradigm for the regulation of megakaryocyte development and platelet production via the Hippo signaling pathway, and suggest the potential use of an FDA-approved drug to induce higher platelet production in cultured cells.
Highlights
Patients with life-threatening thrombocytopenic bleeding require platelet transfusion support
We previously demonstrated that Hippo pathway core kinase LATS1/2 plays an essential role in regulating megakaryocyte proliferation and differentiation [4]
We generated YAP-KD, TAZ-KD, and YAP/TAZ KD cell lines in MEG-01 cells, and used them to determine the effect of YAP and/or TAZ on megakaryoblastic cell differentiation and platelet production
Summary
Patients with life-threatening thrombocytopenic bleeding require platelet transfusion support. Single donor rather than pooled platelet is the most ideal transfusion product choice because the likelihood of developing alloimmunization and/or infection is lower. An approach of current interest is in vitro production of platelets from a single donor. It was estimated that one megakaryocyte could generate and release a few thousand platelets in vivo [1,2,3]. Poor platelet release was commonly observed when megakaryocytes were cultured in vitro. Better understanding of the factor(s) that affect megakaryocyte proliferation and differentiation is needed to facilitate the development of a new culture system to enhance platelet-like particle (PLP) production from cultured megakaryocytes
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