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Mosaicism Mechanisms in Preimplantation Embryos
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
Maurizio Poli, Antonio Capalbo
Incidence of mosaicism in human fetuses was reported to be lower than 0.5% [29]. When CVS testing or amniocentesis were followed up, no differences were reported in incidence of mosaicism between natural and IVF pregnancies [29,30]. These results suggest that IVF-related procedures are not an independent risk factor for the occurrence of mosaicism in preimplantation embryos. However, this evidence is in sharp contrast with the high incidence reported from PGT-A studies. It has been hypothesized that in a mosaic embryo, chromosomally abnormal cells may be selectively depleted during development, leading to an organism composed of euploid cells only [31,32]. A euploid lineage selection process was demonstrated in a murine model by Bolton and colleagues [33]. However, similar mechanisms in human embryos are still to be demonstrated. In addition, since aneuploidy in murines is not as frequent as in humans, mitotic errors in chromosome segregation had to be induced with administration of an exogenous compound (e.g., reversine). It is a possibility that the internalization of this chemical had a lethal effect on the cell, which was then depleted from the developing embryo not because of an aneuploidy self-detection mechanism but rather due to the cytotoxic effect of the compound. In addition, reversine treatment was shown to induce complex chromosomal alterations [33], instead of single aneuploidies, which are more common in human blastocysts [34]. For this reason, it is possible that the presence of complex abnormalities would result in cell cycle arrest, thus depleting aneuploid cells from the embryo. Although some of the data published suggest no preferential allocation of abnormal cells in specific cell lineages in human mosaic embryos [35], at present, no evidence about the existence of a correction/depletion mechanism of aneuploid through developmental progression has been reported. It is well documented how every chromosome can be found in an abnormal copy number (including full haploid configuration) in embryos at the blastocyst stage [7]. A large set of aneuploidies are also compatible with sustained implantation [36]. These observations suggest that a depletive mechanism targeting aneuploid cells in mosaic embryos after embryo genome activation (EGA) cannot alone explain either the significant reduction in mosaicism diagnosis in blastocyst-stage embryos compared to cleavage stage ones or the extremely low incidence of mosaicism in miscarried products of conception (POC).
The thrombopoietin receptor: revisiting the master regulator of platelet production
Published in Platelets, 2021
Ian S. Hitchcock, Maximillian Hafer, Veena Sangkhae, Julie A. Tucker
MPL is expressed by HSCs from the earliest stage of development[48] and is critical for megakaryocyte development[50]. Decreased receptor expression or function can cause severe thrombocytopenia in humans[49], a phenotype recapitulated by Mpl-null mice, which have only ~5-10% the number of megakaryocytes and circulating platelets compared to wild-type animals[50]. Evidence suggests the primary role of TPO-MPL is to promote megakaryocyte lineage selection in myeloid progenitor cells, rather than differentiation of more mature megakaryocytes. In mice, ablation of Mpl specifically in the megakaryocyte lineage (Mpl-floxed/Pf4cre) not only failed to reduce platelet count, but actually drove myeloproliferation, presumably as a consequence of ineffective TPO clearance due to absence of MPL on platelets[51]. Interestingly, there is also some evidence that TPO may prime platelets for activation. Increased levels of plasma TPO in patients with unstable angina appears to increase monocyte-platelet aggregates and enhances platelet aggregation in response to certain agonists [52,53]. Fortunately, however, there is no evidence of an increased risk of thrombosis in patients receiving TPO agonists [54,55].
B cells and upper airway disease: allergic rhinitis and chronic rhinosinusitis with nasal polyps evaluated
Published in Expert Review of Clinical Immunology, 2021
Harsha H Kariyawasam, Louisa K James
AR is defined by a T2 high inflammatory endotype. T2 inflammation is characterized by tissue Th2 cell and type 2 innate lymphoid cells (ILC2s) dominance, with excess eosinophils and polyclonal IgE production. IL-4, IL-13, and IL-5 are key cytokines that drive T2 inflammation. CD4+ Th2-cell lineage selection and polarization to effector Th2 cells is via IL-4 [11]. Th2 survival is also IL-4 dependent [12,13]. IL-4 induction of endothelial adhesion molecules ICAM-1 and VCAM-1 expression is critical for blood eosinophil tissue extravasation [14,15]. It is IL-4 that determines B-cell immunoglobulin class switching to IgE production [16,17]. IL-13 has significant overlap with IL-4 in terms of influencing B-cell function [18], in particular with B-cell immunoglobulin class switching to IgE production [19]. IL-13 can regulate eosinophil trafficking into tissue [16]. IL-5 is the key cytokine that drives eosinophil differentiation, activation, and survival. IL-13 promotes eosinophilic states via the induction of IL-5 and eotaxin-3 synthesis [20,21]. Potent epithelial innate injury-generated cytokines TSLP, IL-25, and IL-33 stimulate ILC2s to release large amounts of IL-5 and IL-13 but also IL-4, adding to marked immune amplification and sustaining autoinflammatory loops, which in turn determine disease severity and aspects of treatment refractoriness.
In vitro study of the effects of DC electric fields on cell activities and gene expression in human choriocarcinoma cells
Published in Electromagnetic Biology and Medicine, 2021
Jinxin Chen, Linbo Guan, Ping Fan, Xinghui Liu, Rui Liu, Yu Liu, Huai Bai
There are some implications or translatable potentials of applied EF in the cancer area. For example, several types of cancer cells such as prostate cancer, breast cancer, and lung cancer cells are known to migrate directionally under DC EF, and the degree of electrotaxis of these cancer cells has been shown to correlate with their metastatic abilities (Djamgoz et al. 2001; Huang et al. 2009; Pu et al. 2007; Yan et al. 2009). Based on these features, one can develop electric methods to prevent the directed migration of tumor cells, which is an early feature of metastasis. In addition, there are several other EF-controlled, important cell biological events such as proliferation, spindle orientation, cell differentiation, and cell lineage selection. Gaining a deeper understanding of these control mechanisms is likely to offer novel therapeutic approaches for numerous pathologies, including several cancers.