Intracellular Ca2+ Concentration and Phosphatidylserine Exposure in Healthy Human Erythrocytes in Dependence on in vivo Cell Age.

Ingolf Bernhardt,Lars Kaestner,Mauro C Wesseling,Duc Bach Nguyen

doi:10.3389/fphys.2019.01629

Abstract

After about 120 days of circulation in the blood stream, erythrocytes are cleared by macrophages in the spleen and the liver. The “eat me” signal of this event is thought to be the translocation of phosphatidylserine from the inner to the outer membrane leaflet due to activation of the scramblase, while the flippase is inactivated. Both processes are triggered by an increased intracellular Ca2+ concentration. Although this is not the only mechanism involved in erythrocyte clearance, in this minireview, we focus on the following questions: Is the intracellular-free Ca2+ concentration and hence phosphatidylserine exposure dependent on the erythrocyte age, i.e. is the Ca2+ concentration, progressively raising during the erythrocyte aging in vivo? Can putative differences in intracellular Ca2+ and exposure of phosphatidylserine to the outer membrane leaflet be measured in age separated cell populations? Literature research revealed less than dozen of such publications with vastly contradicting results for the Ca2+ concentrations but consistency for a lack of change for the phosphatidylserine exposure. Additionally, we performed reanalysis of published data resulting in an ostensive illustration of the situation described above. Relating these results to erythrocyte physiology and biochemistry, we can conclude that the variation of the intracellular free Ca2+ concentration is limited with 10 μM as the upper level of the concentration. Furthermore, we propose the hypothesis that variations in measured Ca2+ concentrations may to a large extent depend on the experimental conditions applied but reflect a putatively changed Ca2+ susceptibility of erythrocytes in dependence of in vivo cell age.

Highlights

The formation of erythrocytes named erythropoiesis takes about 7 days (Silbernagel and Despopoulus, 2007)
We focus on healthy human erythrocytes and refer to primarily in vivo conditions, explicitly excluding processes occurring during erythrocyte storage in particular storage lesions (Flatt et al, 2014; Petkova-Kirova et al, 2018)
In a variety of reports, we have described possible mechanisms leading to an increased intracellular Ca2+ content of erythrocytes, mainly based on the activity of ion channels (Kaestner et al, 2000; Kaestner and Bernhardt, 2002; Wagner-Britz et al, 2013; Fermo et al, 2017; Danielczok et al, 2017; Rotordam et al, 2019; for a recent review see Kaestner et al, 2020)

Summary

Introduction

The formation of erythrocytes named erythropoiesis takes about 7 days (Silbernagel and Despopoulus, 2007). We provide the context and a literature review about reports investigating if there is an in vivo age dependence of the intracellular Ca2+ concentration and phosphatidylserine exposure in healthy human erythrocytes.

Results

Conclusion