Kim Hyunjun, Jarocha Danuta, Johnson Ian, Ahn Hyunsook, Hlinka Nicholas, French Deborah L, Rauova Lubica, Lee Kiwon, Poncz Mortimer
bioRxiv. 2024 Jun 4:2024.06.04.597316. doi: 10.1101/2024.06.04.597316.
Many aspects of thrombopoiesis, the release of platelets from megakaryocytes (Mks), remain under debate, including where this process occurs. Murine lung -microscopy studies suggested that a significant fraction of circulating platelets were released from lung-entrapped, marrow-derived Mks. We now confirm these studies that endogenous mMks are entrapped in the lungs and show that intravenously infused -differentiated, mature murine (m) and human (h) Mks are similarly entrapped followed by shedding of their cytoplasm over ∼30 minutes with a peak number of released platelets occurring 1.5-4 hours later. However, while infused Mks from both species shed large intrapulmonary cytoplasmic fragments that underwent further processing into platelet-sized fragments, the two differed: many mMks escaped from and then recycled back to the lungs, while most hMks were enucleated upon first intrapulmonary passage. Infused immature hMks, inflammatory hMks, umbilical cord-blood-derived hMks and immortalized Mk progenitor cell (imMKCL)-derived hMks were also entrapped in the lung of recipient mice, and released their cytoplasm, but did so to different degrees. Intraarterial infused hMks resulted in few Mks being entrapped in tissues other than the lungs and was accompanied by a blunted and delayed rise in circulating human platelets. These studies demonstrate that the lung entraps and processes both circulating Mks and released large cytoplasmic fragments consistent with a recent lung/heart murine study and support a pulmonary-centric "catch-and-release" model of thrombopoiesis. Thus, thrombopoiesis is a drawn-out process with the majority of cytoplasmic processing derived from Mks occurring in the pulmonary bed.
Infused -differentiated megakaryocytes synchronously release cytoplasmic fragments highly selectively in the pulmonary bed. Large, released megakaryocyte fragments recycle to the lungs, undergo further fission, terminally form platelets.
血小板生成（即巨核细胞释放血小板的过程）的许多方面仍存在争议，包括该过程发生的位置。小鼠肺部显微镜研究表明，相当一部分循环血小板是由肺内捕获的骨髓源性巨核细胞释放的。我们现在证实了这些研究，即内源性小鼠巨核细胞被困在肺中，并表明静脉注射分化的、成熟的小鼠和人类巨核细胞同样会被困住，随后在约30分钟内其细胞质脱落，释放的血小板数量在1.5 - 4小时后达到峰值。然而，虽然两种物种注入的巨核细胞都会在肺内脱落大的细胞质片段，这些片段会进一步加工成血小板大小的片段，但两者存在差异：许多小鼠巨核细胞从肺中逸出然后再循环回到肺中，而大多数人类巨核细胞在首次进入肺时就去核了。注入的未成熟人类巨核细胞、炎性人类巨核细胞、脐带血来源的人类巨核细胞和永生化巨核细胞祖细胞来源的人类巨核细胞也被困在受体小鼠的肺中，并释放其细胞质，但程度不同。动脉内注入人类巨核细胞导致很少有巨核细胞被困在肺部以外的组织中，并伴随着循环人类血小板的升高减弱和延迟。这些研究表明，肺捕获并处理循环中的巨核细胞和释放的大细胞质片段，这与最近一项小鼠肺/心脏研究一致，并支持以肺为中心的血小板生成“捕获 - 释放”模型。因此，血小板生成是一个漫长的过程，巨核细胞的大部分细胞质加工发生在肺床。
注入的分化巨核细胞在肺床中高度选择性地同步释放细胞质片段。释放的大巨核细胞片段循环回到肺中，经历进一步裂变，最终形成血小板。
