The Genetic and Biochemical Blueprint of Endometrial Receptivity: Past, Present, and Future Factors Involved in Embryo Implantation Success

In the field of assisted reproductive technology, endometrial receptivity is a crucial aspect that affects implantation rates in in-vitro fertilization procedures; in fact, impaired endometrial receptivity has been identified as the rate-limiting step for favorable pregnancy outcomes once factors regarding embryo quality have been optimized. The endometrium is a dynamic tissue that undergoes proliferative and secretory changes in each menstrual cycle, acquiring a short and transient period of embryo receptivity known as the Window of Implantation. Precise embryo-endometrial synchrony is necessary to achieve a successful pregnancy, and it involves complex and multifactorial processes related to morphological, biochemical, and genetic changes. On that behalf, defining the receptive window of each patient for personalized embryo transfer is a current goal. Here, we review different indicators of endometrial receptivity throughout the menstrual cycle, spotlighting the opening of the window of implantation: classical histological and biochemical markers, genetic factors, leading-edge transcriptomic signatures and miRNA profiles, and novel features such as the microbiome and secretome. Understanding the molecular mechanisms behind endometrial receptivity will facilitate the optimization and improvement of infertility treatments

Aneuploidy Rates Inversely Correlate with Implantation during <em>In Vitro</em> Fertilization Procedures: In Favor of PGT

Aneuploidy, the hold of an abnormal number of chromosomes that differs from the normal karyotype, is a recognized leading cause of miscarriage and congenital disabilities. In human gametes and embryos, aneuploidy rates are prevalent, and these rates increase with advanced maternal age; additionally, it has been suggested that hormonal stimulation for achieving in vitro fertilization (IVF) protocols further increases aneuploidy rates. Although about 65% of chromosomally abnormal embryos culminate in spontaneous miscarriages, there is still evidence of live births harboring crucial aneuploidies. Furthermore, although some frequent aneuploidies are consistent, others differ between countries, making it harder to focus on a specific set of anomalies but vital to focus regionally on those more prevalent. Preimplantation genetic testing (PGT) is a highly endorsed technique in assisted reproductive treatments to evaluate possible embryo aneuploidies, genetic defects, and congenital disorders. On this subject, this study shows that IVF aneuploidy rates in embryo cohorts of high morphological quality are inversely associated with implantation rates. In its entirety, this study reinforces the utility of PGT for embryo evaluation

Notch Signaling in the Astroglial Phenotype: Relevance to Glutamatergic Transmission

Glutamate (Glu), the major excitatory neurotransmitter, elicits its action through the activation of membrane receptors and transporters expressed in neurons and glial cells. Glial glutamate transporters, EAAT1 and EAAT2, remove this transmitter from the synaptic cleft preventing an excitotoxic insult. The Notch pathway is a signaling system involved in neuro- and gliogenesis. Radial glia (RG) generates neurons, oligodendrocytes, and astrocytes in a spatial and temporal pattern, in which Notch represses neurogenesis, maintaining the self-renewal potential of RG. Astrogenesis depends on several stimuli, Notch being a master regulator of the differentiation process. The cAMP-PKA-CREB signaling cascade cross talks with the Notch pathway, acting synergistically by reducing progenitor markers and inducing astrocytic differentiation. Notch1 mRNA is upregulated in a PKA/γ-secretase/NICD/CSL-dependent manner, suggesting a feedback loop to keep Notch active until astrocytic differentiation is complete. Glial differentiation is also modulated by PKC, which acts over NICD. In RG cells and astrocytes enwrapping glutamatergic synapses, EAAT1 transcriptional regulation is mediated by PKC, increasing Notch expression and its receptor intracellular traffic. It is clear that Notch represents an activity-dependent molecular key in RG cells that enable them to shape glutamatergic transmission through the expression of genes involved in glial/neuronal interactions

The patent landscape in the field of stem cell therapy: closing the gap between research and clinic [version 4; peer review: 2 approved]

Stem cell technology is a powerful tool ready to respond to the needs of modern medicine that is experiencing rapid technological development. Given its potential in therapeutic applications, intellectual property rights (IPR) as a protection resource of knowledge are a relevant topic. Patent eligibility of stem cells has been controversial as restrictions to access the fundamental technologies open a gap between research and clinic. Therefore, we depicted the current patent landscape in the field to discuss if this approach moves forward in closing this breach by examining patent activity over the last decade from a transdisciplinary perspective. Stem cell therapeutic applications is an area of continuous growth where patent filing through the PCT is the preferred strategy. Patenting activity is concentrated in the USA, European Union, and Australia; this accumulation in a few key players leads to governance, regulation, and inequality concerns. To boost wealthiness and welfare in society - stem cell therapies' ultimate goal - while at post-pandemic recovery, critical elements in the field of IPR rise to overcome current limitations: to promote bridge builders able to connect the research and business worlds, regulatory updates, novel financing models, new vehicles (startups, spinouts, and spin-offs), and alternative figures of intellectual property

EAAT1-dependent Transcriptional Control depends on the Substrate Translocation Process

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is removed from the synaptic cleft by a family of sodium-dependent transporters expressed in neurons and glial cells. The bulk of glutamate uptake activity occurs in glial cells through the sodium-dependent glutamate/aspartate transporter (EAAT1/GLAST) and glutamate transporter 1 (EAAT2/GLT-1). EAAT1/GLAST is the predominant transporter within the cerebellum. It is highly enriched in Bergmann glial cells that span the cerebellar cortex and wrap the most abundant glutamatergic synapses in the central nervous system, the synapse formed by the parallel fibers and the Purkinje cells. In the past years, it has become evident that Bergmann glial cells are involved in glutamatergic transmission. Glutamate transporters are tightly regulated due to their essential role in tripartite synapses. Glutamate regulates EAAT1/GLAST function and gene expression in a receptor-dependent and receptor-independent manner. Through the use of the non-metabolizable EAAT1/GLAST ligand, D-Aspartate, and the well-established chick cerebellar Bergmann glia primary culture, in this contribution, we demonstrate that EAAT1/GLAST down-regulates its expression and function at the transcriptional level through the activation of a signaling pathway that includes the phosphatidyl inositol 3 kinase (PI3K), the Ca 2+ /diacylglycerol dependent protein kinase PKC and the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). These results favor the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells. Summary statement EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells