Biology subjects

Kondrychyn, I.

Publications and source records attributed to Kondrychyn, I..

5 recordsLinked to original sources

bioRxiv2026

Cellular hydraulics ensures robust endothelial-to-haematopoietic transition

Haematopoietic stem and progenitor cells (HSPCs) emerge from specialised haemogenic endothelial cells (HECs) in the ventral wall of the dorsal aorta (VDA) through a process known as endothelial-to-haematopoietic transition (EHT). During EHT, elongated HECs undergo actomyosin-driven rounding and extrusion, a mechanically demanding transformation that requires cell integrity to be maintained. Here, we identify an osmo-hydraulic volume-regulation mechanism that enables HECs to adapt to and withstand this mechanical challenge. Haemodynamic forces increase Piezo-dependent calcium ion activity in ventral endothelial cells, while Piezo activation promotes HEC swelling. Combined genetic and pharmacological analyses support a pathway in which Piezo-mediated swelling triggers VRAC-dependent osmolyte efflux and Aqp1a.1-mediated water efflux to reduce HEC volume. Disrupting either osmolyte or water efflux causes excessive HEC swelling, compromises HEC integrity and reduces HSPC production. Together, our findings establish osmo-hydraulic volume regulation as a mechanism that preserves cellular robustness during EHT and support a model in which aquaporins act as pressure-relief valves, dissipating intracellular hydrostatic pressure to sustain HEC survival and definitive haematopoiesis.

cell biology↗

bioRxiv2024

Circumferential actomyosin bundles drive endothelial cell deformations to constrict blood vessels

Following the formation of new blood vessels, vascular remodelling ensues to generate a hierarchical network of vascular tubes with optimal connections and diameters for efficient blood perfusion of tissues. How transitions in endothelial cell (EC) number and shape are coordinated to define vessel diameter during development remains an open question. In this study, we discovered EC deformations, rearrangements and transient formation of self-seam junctions as key mechanisms that explain a negative relationship between cell number and vessel diameter. High-resolution analysis of actin cytoskeleton organization disclosed the generation of tension-bearing, circumferential actomyosin bundles in the endothelial cortex that drive EC deformation and vessel constriction. Importantly, the loss of circumferential actin bundles in krit1/ccm1-deficient ECs causes cell enlargement and impaired vessel constriction that culminate in dilated vessels, characteristic of cerebral cavernous malformation. Our multiscale study therefore underpins circumferential actomyosin-driven EC deformations in controlling vessel size and in the prevention of vascular malformations.

cell biology↗

bioRxiv2024

Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis

Cell migration is a key process in the shaping and formation of tissues. During sprouting angiogenesis, endothelial tip cells invade avascular tissues by generating actomyosin-dependent forces that drive cell migration and vascular expansion. Surprisingly, ECs can still invade if actin polymerization is inhibited. In this study, we show that endothelial tip cells employ an alternative mechanism of cell migration that is dependent on Aquaporin (Aqp)-mediated water inflow and increase in hydrostatic pressure. In the zebrafish, ECs express aqp1a.1 and aqp8a.1 in newly formed vascular sprouts in a VEGFR2-dependent manner. Aqp1a.1 and Aqp8a.1 loss-of-function studies show an impairment in intersegmental vessels formation because of a decreased capacity of tip cells to increase their cytoplasmic volume and generate membrane protrusions, leading to delayed tip cell emergence from the dorsal aorta and slower migration. Further inhibition of actin polymerization resulted in a greater decrease in sprouting angiogenesis, indicating that ECs employ two mechanisms for robust cell migration in vivo. Our study thus highlights an important role of hydrostatic pressure in tissue morphogenesis.

developmental biology↗

bioRxiv2020

High behavioural variability mediated by altered neuronal excitability in auts2 mutant zebrafish

Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 (AUTS2) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. Yet, the function of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. Auts2a-/- zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with high trial-to-trial variability in the latency. We demonstrate that this is due to the reduced excitability of Mauthner neurons resulting in unreliable firing with stimuli that normally elicit the escape response. Combined with previous studies that show Auts2-regulation of the transcription of ion channel proteins, our results suggest that Auts2 sets the excitability of neurons by activating a set transcriptional program. Significance statementAUTS2 is one among recently identified autism susceptibility candidate genes, whose function in neuronal circuits is unclear. Using zebrafish as a model organism, we probe the function of Auts2a (homolog of mammalian AUTS2) at the cellular, network and behavioral levels. The escape behavior of Auts2a mutant zebrafish is highly variable with normal short latency escapes, long latency escapes and total failures across trials in the same fish. This occurs because neuronal excitability is inappropriately set in the Mauthner neurons of mutants leading to the large trial-to-trial variability in responses. The behavioral variability is fully explained by variability in firing action potentials in the Mauthner neuron, providing an integrative understanding of how behavioral variability arises from mutations at the genetic level.

neuroscience↗

bioRxiv2020

Marcksl1 modulates endothelial cell mechanoresponse to haemodynamic forces to control blood vessel shape and size

The formation of vascular tubes is driven by extensive changes in endothelial cell (EC) shape. Here, we have identified a novel role of the actin-binding protein, Marcksl1, in modulating the mechanical properties of EC cortex to regulate cell shape and vessel structure during angiogenesis. Increasing and depleting Marcksl1 expression level in vivo resulted in an increase and decrease, respectively, in EC size and the diameter of microvessels. Furthermore, endothelial overexpression of Marcksl1 induced ectopic blebbing on both apical and basal membranes, during and after lumen formation, that is suppressed by reduced blood flow. High resolution imaging revealed that Marcksl1 promotes the formation of linear actin bundles and decreases actin density at the EC cortex. Our findings demonstrate that a balanced network of linear and branched actin at the EC cortex is essential in conferring cortical integrity to resist the deforming forces of blood flow to regulate vessel structure.

cell biology↗