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Calcium ions mediate the volume homeostasis of human red blood cells (RBCs) in the circulation. The mechanism by which calcium ions affect RBC hydration states always follows the same sequence. Deformation of RBCs traversing capillaries briefly activates mechanosensitive PIEZO1 channels, allowing Ca2+ influx down its steep inward gradient transiently overcoming the calcium pump and elevating [Ca2+]i. Elevated [Ca2+]i activates the Ca2+-sensitive Gardos channels, inducing KCl loss and cell dehydration, a sequence operated with infinite variations in vivo and under experimental conditions. The selected health and disease themes for this review focus on landmark experimental results that led to the development of highly constrained models of the circulatory changes in RBC homeostasis. Based on model predictions, a new perspective emerged, pointing to PIEZO1 dysfunction as the main trigger in the formation of the profoundly dehydrated irreversible sickle cells, the main pathogenic participants in vaso-occlusion, the root cause of sickle cell disease. [ABSTRACT FROM AUTHOR]

The mechanism of nacre formation in gastropods involves a vesicular system that transports organic and mineral precursors from the mantle epithelium to the mineralization chamber. Between them lies the surface membrane, a thick organic structure that covers the mineralization chamber and the forming nacre. The surface membrane is a dynamic structure that grows by the addition of vesicles on the outer side and recedes by the formation of interlamellar membranes on the inner side. By using a combination of electron microscopy imaging and spectroscopy, we have monitored the journey of the vesicles from the mantle epithelium to the mineralization chamber, focusing on the elemental composition of the organic structures at each stage. Our data reveal that transport occurs in lipid bilayer vesicles through exocytosis from the outer mantle epithelium. After release into the surface membrane, chitin undergoes a process of self-assembly and interaction with proteins, resulting in progressive changes of the internal structure of the surface membrane until the final structure of the interlamellar membranes is acquired. Finally, these detach from the inner side of the surface membrane. Elemental analysis revealed the transport of a considerable amount of calcium bound to proteins, likely forming calcium-protein complexes. The formation of nacre tablets occurs through the incorporation of organic and mineral precursors extruded from the mantle epithelium. Although much attention has been paid to the presence of amorphous phases in recent decades, the calcium transport system has not yet been elucidated. We have monitored the packaging of organic and mineral precursors in the form of vesicles from the mantle epithelium to the mineralization chamber. We have shown that the surface membrane represents the zone where chitin and protein polymerization takes place, acquiring the final structure for the formation of interlamellar membranes. Interestingly, these organic structures transport a considerable amount of organic calcium into the mineralization chamber, which support a transport system based on acidic calcium-binding proteins. [Display omitted] [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD), affecting millions worldwide, is caused by the homozygous inheritance of the abnormal haemoglobin, HbS. Deoxygenation of HbS in the venous circulation permeabilizes sickle cells to calcium via PIEZO1 channels triggering a dehydration cascade driven by the outward electrochemical potassium gradient. This mechanism operates with particular intensity in a subpopulation of sickle RBCs, the irreversibly sickled cells (ISCs). The lifespan of ISCs is extremely short, about 4 to 7 days. Most of this time is spent in a profoundly dehydrated condition, the irreversibly sickled state, eliciting vaso-occlusion, which is considered the root cause of organ failure and pain crisis in SCD. There is a large experimental and clinical database on sickle cells and ISCs, but how ISCs form and evolve in the circulation remains a mystery. The present study is the first attempt to unravel the experimentally inaccessible lifecycle of ISCs in vivo applying a well-accredited model of red blood cell homeostasis and circulatory dynamics, using a vast array of validated experimental observations to tightly constrain the model parameters. The results showed that abnormally strong deoxy-PIEZO1 responses were needed for calcium to elicit a violent hyperdense collapse in ISC-destined stress reticulocytes within about a day in the circulation. The potassium-depleted ISCs remain in this maximally dehydrated but volume stable condition, the pathogenic state, sustained by vigorous pump-leak balanced sodium fluxes. Eventually, sodium pump decay initiates rapid terminal rehydration by the unbalanced net gain of NaCl and water. Analysis of the mechanisms behind this three-stage circulatory lifecycle of ISCs exposed a complex web of interactions among many components of the homeostatic fabric of RBCs. These findings point to the abnormally intense PIEZO1 response to deoxygenation in ISC-destined stress reticulocytes as a prime cause of ISC formation in vivo, a central target for future research., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)