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Arteropathies, Microcirculation and Vasculitis
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Lymphoedema is a chronic and progressive condition that can affect any limb or part of the body and is primarily due to reduced lymphatic transport. The condition can be primary (intrinsic developments), such as lymphatic development, or secondary (extrinsic factors), such as trauma. The oedema leads to a higher risk of infections, such as cellulitis. One of the first genes to be identified as causative agent for the development of lymphoedema was the mutated gene VEGFR3 (vascular endothelial growth factor receptor 3). VEGFR3 mediates lymphangiogenesis in response to growth factors C and D. This mutated autosomal dominant gene is found in Milroy's disease which includes oedema in the feet and lower limbs with hydrocele development in one third of males affected by the condition. Milroy's disease is a rare congenital disease which shows gross and diffuse dilatation of the lymphatics. Other mutated genes include PIEZO1 which is an autosomal recessive gene responsible for generalized lymphatic dysplasia (GLD). This is a very rare disorder, characterized by multifocal lymphatic malformations in various tissues, that is due to congenital abnormalities of lymphatic development. This has both internal, such as intestinal, and external, such as limb, oedema. Hennekam lymphangiectesia-lymphoedema syndrome (HS) has full body oedema, caused by mutations in CCBE1 and FAT4 genes.
Organoids as an Emerging Tool for Nano-Pharmaceuticals
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Continuous dynamic perturbations/movements contribute to the developmental aspect of cellular organisation and are brought about by the 3D space of the cell. The basic mechanisms for tissue morphogenesis include epithelial-to-mesenchymal transitions (EMT), as well as constrictions at the apical region, contributing to the mechanical forces generated intracellularly. It has been shown that cells of the same type can make a regularised construct, on the basis of specific catenins and cadherins (Steinberg 1963). Similarly, free energy manipulations can help in germ layer speciation (Davis et al. 1997). Moreover, interactions of extracellular matrix (ECM) with cells molecules mediated by integrins are crucial in enabling the movement of large-scale tissues (Bénazéraf et al. 2010). Various molecules of ECM also play a pivotal role in inducing cytoskeletal modifications (Bedzhov and Zernicka-Goetz 2014). Looking at all the levels, starting from a cell level to multicellular levels, these movements contribute in the inception of biophysical fields that signals to regulatory networks. Hippo pathway effector Yap plays an important role in the molecular signalling mechanisms of mechano sensing and mechano transduction (Benham-Pyle et al. 2015). Piezo1/2, gated ion channels produce their effect through Yap translocation (Hennes et al. 2019) or through the cytoskeleton structure (Stewart et al. 2015). The role of Yap translocation is already established in stem cell differentiation (Lian et al. 2010). Piezo1 and Piezo2 have been shown to sense stress directly (Lin et al. 2019). Piezo1 plays an important role in determining lineage in stem cells, activation led to neurogenesis and inhibition differentiated stem cells to astrocytes (Pathak et al. 2014).
Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Multipotent NPCs have three possible fates of differentiation: induction into a neuron, astrocyte, or oligodendrocyte. The ion channels, Piezo1, and TRP channels have been detected in hPSC-derived NPCs, and the former has also been shown to greatly influence the fate of differentiation of these NPCs. Piezo1 is a nonclassical ion channel belonging to the stretch-activated channel (SAC) family, which act as nonspecific cationic channels that can be activated by mechanical force (39,40). It was observed that the Piezo1 ion receptor was able to dictate whether neural progenitor cells differentiated into neurons or astrocytes depending on the stiffness of the experienced mechanical force. The fate of these Piezo1-expressing NPCs was determined by the stiffness of their local environment, such as the force exerted by the ECM or adjacent cells (41). The stiffness regulated the elicited inward calcium transient which directed the fate of NPCs. Increasing the stiffness led to an increase in the calcium transient which directed the NPCs toward neurogenesis, while a decrease in stiffness caused a lower calcium influx resulting in an astrocytic fate (41). The canonical transient receptor potential (TRPC) channel was also found to be present in NPCs and its function was implicated in transient calcium influx which controls cell proliferation in NE cells. Transient calcium influx was reduced significantly in hPSC-derived NE cells upon application of TRPC antagonists (42). These findings have implications in developing NPC-based stem cell regenerative medicine, in which NPCs can be transplanted to promote neural repair. Manipulation of Piezo1 channel in NPCs may control their fate after implantation to achieve optimal regenerative effects under disease conditions, while the manipulation of TRPC channels can be used to study their functions in neurodevelopment.
Computational modeling of stretch induced calcium signaling at the apical membrane domain in umbrella cells
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
Amritanshu Gupta, Rohit Manchanda
A key characteristic of Piezo1 currents is their inactivation even in the presence of a sustained mechanical stimulus. In recent years, the structural determinant of inactivation within the channel pore has been investigated (Zheng et al. 2019). However, their link to biophysical attributes (if any) remains to be elucidated. Towards modelling the inactivation kinetics, we found studies reporting that Piezo1 currents decay with a characteristic time constant of ∼15 ms (Dubin et al. 2017; Wu et al. 2017). We, therefore, modelled the inactivating gating variable fPz as a decaying exponential function with τdecay = 15 ms (Equation 4). Our stretch protocol (Figure 2a) comprises a rising ramp input with the rate of increase in membrane stretch (α), taking on values between 0.1 and 0.6 depending on the final net-stretch value for the membrane, which ranged between 1 and 6 μm. In Equation (4), ton represents the time instant when the full-strength stretch stimulus is reached. This includes an adaptation period of 2 ms equal to the activation time constant for the Piezo1 conductance. toff represents the time instant corresponding to the end of the stretch stimulus. Parameter values associated with the Piezo1 gating variables dPz and fPz can be found in Table A.1 in the supplementary material.
Are PIEZO1 channels a potential therapeutic target for heart failure? Getting to the heart of the matter
Published in Expert Opinion on Therapeutic Targets, 2023
PIEZO1 is not specific to the heart [6] but may rather be an almost ubiquitous force-sensing cassette of many cell types throughout the body. In part this could be beneficial for a PIEZO1 antagonist strategy because PIEZO1 is also in cardiac fibroblasts, where it drives the release of inflammatory and remodeling factors [13,15]. The role of this PIEZO1 in models of heart failure is unknown, but its inhibition is expected to be protective against adverse cardiac remodeling. However, PIEZO1 antagonists might also have concerning extra-cardiac effects. PIEZO1 loss-of-function mutations are associated with a rare form of lymphedema [17], so a potential unwanted effect of antagonists is fluid retention, which can already be a problem in heart failure patients. These familial genetic studies of lymphedema also show us that the complete absence of PIEZO1 can be compatible with life and that its partial loss (due to haploinsufficiency or heterozygous disruptive mutation) can lack obvious adverse effects at least in early adult life [17]. Therefore, antagonism of physiological PIEZO1 might not be a major problem until there is at least 50% channel inhibition (Figure 1), a percentage estimated based on its potential equivalence to the effect of PIEZO1 haploinsufficiency.
Hereditary red blood cell membrane defects. Detection of PIEZO1 mutations associated with SPTA1 mutations. An unusual clinical case of hereditary xerocytosis
Published in Pediatric Hematology and Oncology, 2020
Carmelo Fortugno, Eulalia Galea, Renato Cantaffa, Francesco Gigliotti, Rachele Lucia Fabiano, Valentina Talarico, Giuseppe Raiola, Maria Concetta Galati
We are dealing with a very complex case. The only certainty at the moment is the diagnosis of Hereditary xerocytosis linked to the PIEZO1 mutation. Phenotypically, the case has Hereditary spherocytosis characteristics. For a more accurate diagnosis it would be useful to know, if the two SPTA1 mutations were inherited in cis or in trans, but the parents refuse to undergo any further investigation at the moment. It appears that the multiple mutations found have an additive impact on the phenotypic manifestations and makes some considerations necessary. In particular: 1) Although it is known that the need for transfusions in patients with congenital hemolytic anemia tends to decrease beyond the first year of life, this case we are not able to predict whether the presence of two concomitant conditions can determine a prolonged transfusion-dependence. 2) Hereditary xerocytosis is notoriously associated with a greater tendency to iron overload, regardless of the transfusion load. This makes an optimal chelation program guided by the ferritin values indispensable and, as soon as possible, by instrumental investigations that evaluate the visceral iron accumulation (T2* MRI). 3) Therapeutic splenectomy is contra-indicated in Hereditary xerocytosis because it could significantly increase the risk of deep vein thrombosis without an appreciable increase in hemoglobin levels. However in our case it will be carefully evaluated as a therapeutic option, carefully evaluating the risk/benefit ratio.