Biology subjects

Kaestner, L.

Publications and source records attributed to Kaestner, L..

4 recordsLinked to original sources

bioRxiv2023

Terminal maturation of human reticulocytes to red blood cells by extensive remodelling and progressive liquid ordering of membrane lipids

In the age of "omics", lipidomics of erythropoiesis is still missing. How reticulocytes mature in the circulation into functional erythrocytes is also for the most part unknown, beyond the lipidomics level. We have characterized here the lipid content of two subpopulations of peripheral reticulocytes of different maturity and three of erythrocytes of different age. Reticulocytes undergo profound changes in membrane lipid composition as they mature in the vasculature. Sphingomyelin and cholesterol increase, whereas phosphatidylcholine and phosphatidylserine decrease, relative to total lipids, from young reticulocytes to mature erythrocytes, suggesting that the area of the membrane in liquid-ordered state increases. The relative amounts of the more than 70 phospholipid subclasses evaluated here also change in the process. As peripheral reticulocytes and erythrocytes are unable of de-novo phospholipid synthesis, such remodeling likely requires selective removal of phospholipids from the membrane or their exchange with plasma or both. It has to be investigated whether this process might involve lipid transfer proteins that, when defective, such as in neuroacantocytosis syndromes, result in altered erythrocyte morphology. These findings not only shed light on fundamental aspects of red blood cell physiology and erythropoiesis but also raise intriguing questions surrounding protein-lipid interactions, membrane architecture, and lipid trafficking mechanisms.

biochemistry↗

bioRxiv2022

Red blood cell lingering modulates hematocrit distribution in the microcirculation

The distribution of red blood cells (RBCs) in the microcirculation determines the oxygen delivery and solute transport to tissues. This process relies on the partitioning of RBCs at successive bifurcations throughout the microvascular network and it is known since the last century that RBCs partition disproportionately to the fractional blood flow rate, therefore leading to heterogeneity of the hematocrit (i.e. volume fraction of RBCs in blood) in microvessels. Usually, downstream of a microvascular bifurcation, the vessel branch with a higher fraction of blood flow receives an even higher fraction of RBC flux. However, both temporal and time-average deviations from this phaseseparation law have been observed in recent works. Here, we quantify how the microscopic behavior of RBCs lingering (i.e. RBCs temporarily residing near the bifurcation apex with diminished velocity) influences their partitioning, through combined in vivo experiments and in silico simulations. We developed an approach to quantify the cell lingering at highly-confined capillary-level bifurcations and demonstrate that it correlates with deviations of the phase-separation process from established empirical predictions by Pries et al. Furthermore, we shed light on how the bifurcation geometry and cell membrane rigidity can affect the lingering behavior of RBCs, e.g. rigid cells tend to linger less than softer ones. Taken together, RBC lingering is an important mechanism that should be considered when studying how abnormal RBC rigidity in diseases such as malaria and sickle-cell disease could hinder the microcirculatory blood flow or how the vascular networks are altered under pathological conditions (e.g. thrombosis, aneurysm).

biophysics↗

bioRxiv2021

Changes in blood cell deformability in Chorea-Acanthocytosis and effects of treatment with dasatinib or lithium

Misshaped red blood cells (RBCs), characterized by thorn-like protrusions known as acanthocytes, are a key diagnostic feature in Chorea-Acanthocytosis (ChAc), a rare neurodegenerative disorder. The altered RBC morphology likely influences their biomechanical properties which are crucial for the cells to pass the microvasculature. Here, we investigated blood cell deformability of 5 ChAc patients compared to healthy controls during up to one-year individual off-label treatment with the tyrosine kinases inhibitor dasatinib or several weeks with lithium. Measurements with two microfluidic techniques allowed us to assess RBC deformability under different shear stresses. Furthermore, we characterized leukocyte stiffness at high shear stresses. The results show that blood cell deformability - including both RBCs and leukocytes - in general is altered in ChAc patients compared to healthy donors. Therefore, this study shows for the first time an impairment of leukocyte properties in ChAc. During treatment with dasatinib or lithium, we observe alterations in RBC deformability and a stiffness increase for leukocytes. The hematological phenotype of ChAc patients hints at a reorganization of the cytoskeleton in blood cells which partly explains the altered mechanical properties observed here. These findings highlight the need for a systematic assessment of the contribution of impaired blood cell mechanics to the clinical manifestation of ChAc.

biophysics↗

bioRxiv2021

Imaging erythrocyte sedimentation in whole blood

The erythrocyte sedimentation rate (ESR) is one of the oldest medical diagnostic tools. However, currently there is some debate on the structure formed by the cells during the sedimentation process. While the conventional view is that erythrocytes sediment as separate aggregates, others have suggested that they form a percolating gel, similar to other colloidal suspensions. A direct probing of the structures formed by erythrocytes in blood at stasis is then required to settle these discrepancies. Here, we report observations performed with three different optical imaging techniques: direct light transmission through thin samples, two-photon microscopy and light-sheet microscopy. All techniques revealed a dynamic structure of a channeling gel but with differences in the resolved details. A quantitative analysis of the erythrocyte related processes and interactions during the sedimentation need a further refinement of the experimental set-ups.

biophysics↗