Human megakaryocytic microparticles induce de novo platelet biogenesis in a wild-type murine model
Human megakaryocytic microparticles induce de novo platelet biogenesis in a wild-type murine model
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DOI：
10.1182/bloodadvances.2019000753
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发表时间：
2020-03-10
期刊：
影响因子：
7.5
通讯作者：
Papoutsakis, Eleftherios T.
中科院分区：
文献类型：
--
作者：
Escobar, Christian;Kao, Chen-Yuan;Papoutsakis, Eleftherios T.
血小板输注用于治疗特发性或药物诱导的血小板减少症。血小板是一种供应有限的昂贵产品，由于不能冷冻，因此储存和分销能力有限。我们已经证明，在体外，人巨核细胞微粒（huMkMPs）靶向人CD 34（+）造血干细胞和祖细胞（huHSPCs），并诱导其Mk分化和血小板生物合成的血小板生成素的情况下。在这项研究中，我们表明，在体外，huMkMPs也可以靶向鼠HSPCs（muHSPCs），诱导他们分化成巨核细胞的血小板生成素的情况下。基于此，我们使用野生型BALB/c小鼠证明，静脉内给予2 × 10（6）huMkMP可触发小鼠血小板新生，在给药后16小时血小板水平增加至49%。与血小板减少小鼠中的血小板计数相比，huMkMPs在给药后16小时还通过使血小板计数增加51%而在很大程度上挽救了具有诱导性血小板减少症的小鼠中的低血小板水平。在组织质量基础上标准化，生物分布实验显示，在huMkMP给药后24小时，MkMP主要定位于骨髓、肺和肝。除骨髓外，CD 41（+）（巨核细胞和MK-祖细胞）细胞常见于肺、脾，尤其是肝。在肝脏中，输注的huMKMP与Mk祖细胞和muHSPC共定位，从而表明huMkMP与muHSPC在体内相互作用以诱导血小板生物发生。我们的数据证明了可以冷冻储存的huMkMP治疗血小板减少症并作为体内靶向特异性货物递送至HSPC的有效载体的潜力。
Platelet transfusions are used to treat idiopathic or drug-induced thrombocytopenia. Platelets are an expensive product in limited supply, with limited storage and distribution capabilities because they cannot be frozen. We have demonstrated that, in vitro, human megakaryocytic microparticles (huMkMPs) target human CD34(+) hematopoietic stem and progenitor cells (huHSPCs) and induce their Mk differentiation and platelet biogenesis in the absence of thrombopoietin. In this study, we showed that, in vitro, huMkMPs can also target murine HSPCs (muHSPCs) to induce them to differentiate into megakaryocytes in the absence of thrombopoietin. Based on that, using wild-type BALB/c mice, we demonstrated that intravenously administering 2 x 10(6) huMkMPs triggered de novo murine platelet biogenesis to increase platelet levels up to 49% 16 hours after administration. huMkMPs also largely rescued low platelet levels in mice with induced thrombocytopenia 16 hours after administration by increasing platelet counts by 51%, compared with platelet counts in thrombocytopenic mice. Normalized on a tissue-mass basis, biodistribution experiments show that MkMPs localized largely to the bone marrow, lungs, and liver 24 hours after huMkMP administration. Beyond the bone marrow, CD41(+) (megakaryocytes and Mk-progenitor) cells were frequent in lungs, spleen, and especially, liver. In the liver, infused huMKMPs colocalized with Mk progenitors and muHSPCs, thus suggesting that huMkMPs interact with muHSPCs in vivo to induce platelet biogenesis. Our data demonstrate the potential of huMkMPs, which can be stored frozen, to treat thrombocytopenias and serve as effective carriers for in vivo, target-specific cargo delivery to HSPCs.