School of Computing Science, University of Glasgow, Glasgow, United Kingdom.
Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge, United Kingdom.
PLoS Comput Biol. 2021 Mar 10;17(3):e1008496. doi: 10.1371/journal.pcbi.1008496. eCollection 2021 Mar.
Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The unknown mechanisms by which this is achieved are the subject of this investigation. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the previous paper to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the range of acceptable model outcomes. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the previous paper. The first unexpected finding was that quantal density changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, suggestive of a selective mechanism enabling the extended longevity of RBCs. The densification pattern over most of the circulatory lifespan was determined by calcium pump decay whereas late density reversal was shaped by the pattern of Na/K pump decay. A third finding was that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. A fourth new finding revealed that RBCs exposed to levels of PIEZO1-medited calcium permeation above certain thresholds in the circulation could develop a pattern of early or late hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results reproduced the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.
人类的红细胞（RBC）的循环寿命约为四个月。在持续的氧化和机械压力下，但缺乏细胞器和蛋白质更新的生物合成能力，RBC 会经历大量的体内平衡变化，包括逐渐致密化，随后在其他方面出现晚期密度反转等，这些变化被认为是进化所利用的，以尽可能长时间地维持 RBC 的流变学能力。实现这一目标的未知机制是本研究的主题。每个 RBC 每天在毛细血管中穿行 1000 到 2000 次，大约每分钟一次。作为上一篇论文中引入的 RCM 的扩展，开发了一种专门的 RBC 体内平衡寿命模型，以探索在 120 天的标准化寿命期间对重复毛细血管穿越的累积模式的预测，使用实验数据来限制可接受的模型结果范围。如前一篇论文所述，通过细胞/介质体积比升高的时期和短暂的变形诱导的通透性变化来模拟毛细血管穿越，这些通透性变化归因于 PIEZO1 通道介导。第一个意外的发现是，在单个毛细血管穿越过程中产生的量子密度变化在几天后停止积累，并且不能单独解释 RBC 的观察到的逐渐致密化，从而排除了量子假说。第二个意外的发现是，只有通过严格的钙和钠/钾泵活性衰退时间进程的实施，才能模拟 RBC 致密化和晚期反转的记录模式，这表明存在一种选择性机制，使 RBC 的寿命延长。在大部分循环寿命中，致密化模式是由钙泵衰减决定的，而晚期密度反转则由钠/钾泵衰减模式决定。第三个发现是，量子变化和泵衰减机制都有必要解释记录的寿命模式，两者都不单独充分。第四个新发现揭示了，暴露于循环中一定阈值以上的 PIEZO1 介导的钙渗透水平的 RBC 可能会发展出早期或晚期高密度塌陷，然后是延迟的密度反转的模式。在寿命大大缩短的情况下进行测试时，结果重现了不可逆镰状细胞的已知循环命运，镰状细胞是负责血管阻塞和大多数镰状细胞病临床表现的细胞亚群。对结果的分析提供了对健康和疾病中 RBC 体内平衡在循环老化过程中变化的驱动机制的深入新理解。
