ResearchPad - human-biology-and-medicine https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Activated α<sub>IIb</sub>β<sub>3</sub> on platelets mediates flow-dependent NETosis via SLC44A2]]> https://www.researchpad.co/article/elastic_article_13330 Platelets in our blood form clots over sites of injury to stop us from bleeding. Blood clots can also occur in places where they are not needed, such as deep veins in our legs or other regions of the body. Developing such clots – also known as deep vein thrombosis (or DVT for short) – is one of the most common cardiovascular diseases and a major cause of death. Although certain inherited factors have been linked to DVT, the underlying mechanisms of the disease remain poorly understood.

In addition to platelets, the pathological (or dangerous) clots that cause DVT also contain immune cells called neutrophils which fight off bacterial infections. Platelets are recruited to the wall of the vein by a protein called “von Willebrand Factor” (or VWF for short). However, it remained unclear how these recruited platelets interact with neutrophils and whether this promotes the onset of DVT.

To answer this question, Constantinescu-Bercu et al. used a device that mimics the flow of blood to study how human platelets change when they are exposed to VWF. This revealed that VWF ‘primes’ the platelets to interact with neutrophils via a protein called integrin αIIbβ3. Further experiments showed that integrin αIIbβ3 binds to a protein on the surface of neutrophils called SLC44A2. Once the neutrophils interacted with the ‘primed’ platelets, they started making traps which increased the size of the blood clot by capturing other blood cells and proteins.

Finally, Constantinescu-Bercu et al. studied a genetic variant of the SLC44A2 protein which is found in 22% of people and is associated with a lower risk of developing DVT. This genetic mutation caused SLC44A2 to interact with ‘primed’ platelets more weakly, which may explain why people with this genetic variant are protected from getting DVT.

These findings suggest that blocking the interaction between ‘primed’ platelets and neutrophils could reduce the risk of DVT. Although current treatments for DVT can prevent patients from forming dangerous blood clots, they can also cause severe bleeding. Since neutrophils are not crucial for normal blood clots to form at the site of injury, drugs targeting SLC44A2 could inhibit inappropriate clotting without causing excess bleeding.

]]>
<![CDATA[Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline]]> https://www.researchpad.co/article/elastic_article_11928 Muscle cells have storage compartments stuffed full of calcium, which they release to trigger a contraction. This process depends on a channel-shaped protein called the ryanodine receptor, or RYR1 for short. When RYR1 is activated, it releases calcium from storage, which floods the muscle cell. Mutations in the gene that codes for RYR1 in humans cause a group of rare diseases called RYR1-related myopathies. The mutations change calcium release in muscle cells, which can make movement difficult, and make it hard for people to breathe. At the moment, RYR1 myopathies have no treatment.

It is possible that repurposing existing drugs could benefit people with RYR1-related myopathies, but trialing treatments takes time. The fastest and cheapest way to test whether compounds might be effective is to try them on very simple animals, like nematode worms. But even though worms and humans share certain genes, treatments that work for worms do not always work for humans. Luckily, it is sometimes possible to test whether compounds might be effective by trying them out on complex mammals, like mice. Unfortunately, these experiments are slow and expensive. A compromise involves testing on animals such as zebrafish. So far, none of these methods has been successful in discovering treatments for RYR1-related myopathies.

To maximize the strengths of each animal model, Volpatti et al. combined them, developing a fast and powerful way to test new drugs. The first step is an automated screening process that trials thousands of chemicals on nematode worms. This takes just two weeks. The second step is to group the best treatments according to their chemical similarities and test them again in zebrafish. This takes a month. The third and final stage is to test promising chemicals from the zebrafish in mouse muscle cells. Of the thousands of compounds tested here, one group of chemicals stood out – treatments that block the activity of a protein called p38. Volpatti et al. found that blocking the p38 protein, either with drugs or by inactivating the gene that codes for it, changed muscle calcium release. This suggests p38 blockers may have potential as a treatment for RYR1-related myopathies in mammals.

Using three types of animal to test new drugs maximizes the benefits of each model. This type of pipeline could identify new treatments, not just for RYR1-related myopathies, but for other diseases that involve genes or proteins that are similar across species. For RYR1-related myopathies specifically, the next step is to test p38 blocking treatments in mice. This could reveal whether the treatments have the potential to improve symptoms.

]]>
<![CDATA[Intelligent classification of platelet aggregates by agonist type]]> https://www.researchpad.co/article/elastic_article_8130 Platelets are small cells in the blood that primarily help stop bleeding after an injury by sticking together with other blood cells to form a clot that seals the broken blood vessel. Blood clots, however, can sometimes cause harm. For example, if a clot blocks the blood flow to the heart or the brain, it can result in a heart attack or stroke, respectively. Blood clots have also been linked to harmful inflammation and the spread of cancer, and there are now preliminary reports of remarkably high rates of clotting in COVID-19 patients in intensive care units.

A variety of chemicals can cause platelets to stick together. It has long been assumed that it would be impossible to tell apart the clots formed by different chemicals (which are also known as agonists). This is largely because these aggregates all look very similar under a microscope, making it incredibly time consuming for someone to look at enough microscopy images to reliably identify the subtle differences between them. However, finding a way to distinguish the different types of platelet aggregates could lead to better ways to diagnose or treat blood vessel-clogging diseases.

To make this possible, Zhou, Yasumoto et al. have developed a method called the “intelligent platelet aggregate classifier” or iPAC for short. First, numerous clot-causing chemicals were added to separate samples of platelets taken from healthy human blood. The method then involved using high-throughput techniques to take thousands of images of these samples. Then, a sophisticated computer algorithm called a deep learning model analyzed the resulting image dataset and “learned” to distinguish the chemical causes of the platelet aggregates based on subtle differences in their shapes. Finally, Zhou, Yasumoto et al. verified iPAC method’s accuracy using a new set of human platelet samples.

The iPAC method may help scientists studying the steps that lead to clot formation. It may also help clinicians distinguish which clot-causing chemical led to a patient’s heart attack or stroke. This could help them choose whether aspirin or another anti-platelet drug would be the best treatment. But first more studies are needed to confirm whether this method is a useful tool for drug selection or diagnosis.

]]>
<![CDATA[Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome]]> https://www.researchpad.co/article/elastic_article_6336 The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen.

The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs’ cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection.

Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins.

This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease.

This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.

]]>
<![CDATA[Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients]]> https://www.researchpad.co/article/Nb5df6024-f0ef-4660-b81e-c12ec6cc8206 The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1–angiotensin II–angiotensin AT1 receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2–angiotensin(1-7)-angiotensin AT2 receptor and the ACE-2–angiotensin(1-7)–Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.

]]>
<![CDATA[Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation]]> https://www.researchpad.co/article/N58b21af8-f705-4f07-9c06-f212debcae5f A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

]]>
<![CDATA[Role of IL-4 in bone marrow driven dysregulated angiogenesis and age-related macular degeneration]]> https://www.researchpad.co/article/N6f8faaba-59e8-481b-b7e6-5f5712889834 Age-associated sterile inflammation can cause dysregulated choroidal neovascularization (CNV) as age-related macular degeneration (AMD). Intraocular fluid screening of 234 AMD patients identified high levels of IL-4. The purpose of this study was to determine the functional role of IL-4 in CNV formation using murine CNV model. Our results indicate that the IL-4/IL-4 receptors (IL4Rs) controlled tube formation and global proangiogenic responses of bone marrow cells. CCR2+ bone marrow cells were recruited to form very early CNV lesions. IL-4 rapidly induces CCL2, which enhances recruitment of CCR2+ bone marrow cells. This in vivo communication, like quorum-sensing, was followed by the induction of IL-4 by the bone marrow cells during the formation of mature CNVs. For CNV development, IL-4 in bone marrow cells are critically required, and IL-4 directly promotes CNV formation mainly by IL-4R. The IL-4/IL-4Rα axis contributes to pathological angiogenesis through communications with bone marrow cells leading to retinal degeneration.

]]>
<![CDATA[Control of brown adipose tissue adaptation to nutrient stress by the activin receptor ALK7]]> https://www.researchpad.co/article/N8da7d9e7-5767-4b2e-be84-f4c3ee8d6aa6 Adaptation to nutrient availability is crucial for survival. Upon nutritional stress, such as during prolonged fasting or cold exposure, organisms need to balance the feeding of tissues and the maintenance of body temperature. The mechanisms that regulate the adaptation of brown adipose tissue (BAT), a key organ for non-shivering thermogenesis, to variations in nutritional state are not known. Here we report that specific deletion of the activin receptor ALK7 in BAT resulted in fasting-induced hypothermia due to exaggerated catabolic activity in brown adipocytes. After overnight fasting, BAT lacking ALK7 showed increased expression of genes responsive to nutrient stress, including the upstream regulator KLF15, aminoacid catabolizing enzymes, notably proline dehydrogenase (POX), and adipose triglyceride lipase (ATGL), as well as markedly reduced lipid droplet size. In agreement with this, ligand stimulation of ALK7 suppressed POX and KLF15 expression in both mouse and human brown adipocytes. Treatment of mutant mice with the glucocorticoid receptor antagonist RU486 restored KLF15 and POX expression levels in mutant BAT, suggesting that loss of BAT ALK7 results in excessive activation of glucocorticoid signaling upon fasting. These results reveal a novel signaling pathway downstream of ALK7 which regulates the adaptation of BAT to nutrient availability by limiting nutrient stress-induced overactivation of catabolic responses in brown adipocytes.

]]>
<![CDATA[From worms to fish to mice]]> https://www.researchpad.co/article/N38577ced-03dc-45b1-8b00-37d57a5512fc An multi-species approach can be used to identify small molecules with properties that might prove useful for the treatment of some neuromuscular diseases.

]]>
<![CDATA[Yolk-sac-derived macrophages progressively expand in the mouse kidney with age]]> https://www.researchpad.co/article/Nc9607a8e-23e2-4158-a373-7089f452b98a Older people are more likely to develop kidney disease, which increases their risk of having other conditions such as a heart attack or stroke and, in some cases, can lead to their death. Older kidneys are less able to repair themselves after an injury, which may help explain why aging contributes to kidney disease. Another possibility is that older kidneys are more susceptible to excessive inflammation. Learning more about the processes that lead to kidney inflammation in older people might lead to better ways to prevent or treat their kidney disease.

Immune cells called macrophages help protect the body from injury and disease. They do this by triggering inflammation, which aides healing. Too much inflammation can be harmful though, making macrophages a prime suspect in age-related kidney harm. Studying these immune cells in the kidney and how they change over the lifespan could help scientists to better understand age-related kidney disease.

Now, Ide, Yahara et al. show that one type of macrophage is better at multiplying in older kidneys. In the experiments, mice were genetically engineered to make a fluorescent red protein in one kind of macrophage. This allowed Ide, Yahara et al. to track these immune cells as the mice aged. The experiments showed that this subgroup of cells is first produced when the mice are embryos. They stay in the mouse kidneys into adulthood, and are so prolific that, over time, they eventually become the most common macrophage in older kidneys.

The fact that one type of embryonically derived macrophage takes over with age may explain the increased inflammation and reduced repair capacity seen in aging kidneys. More studies will help scientists to understand how these particular cells contribute to age-related changes in susceptibility to kidney disease.

]]>
<![CDATA[A synthetic dataset primer for the biobehavioural sciences to promote reproducibility and hypothesis generation]]> https://www.researchpad.co/article/Nc154045a-ca65-4a9a-bdc2-105149669d9e

Open research data provide considerable scientific, societal, and economic benefits. However, disclosure risks can sometimes limit the sharing of open data, especially in datasets that include sensitive details or information from individuals with rare disorders. This article introduces the concept of synthetic datasets, which is an emerging method originally developed to permit the sharing of confidential census data. Synthetic datasets mimic real datasets by preserving their statistical properties and the relationships between variables. Importantly, this method also reduces disclosure risk to essentially nil as no record in the synthetic dataset represents a real individual. This practical guide with accompanying R script enables biobehavioural researchers to create synthetic datasets and assess their utility via the synthpop R package. By sharing synthetic datasets that mimic original datasets that could not otherwise be made open, researchers can ensure the reproducibility of their results and facilitate data exploration while maintaining participant privacy.

]]>
<![CDATA[Reader engagement with medical content on Wikipedia]]> https://www.researchpad.co/article/N334471ca-16c3-406b-8863-4fe7d1653715

Articles on Wikipedia about health and medicine are maintained by WikiProject Medicine (WPM), and are widely used by health professionals, students and others. We have compared these articles, and reader engagement with them, to other articles on Wikipedia. We found that WPM articles are longer, possess a greater density of external links, and are visited more often than other articles on Wikipedia. Readers of WPM articles are more likely to hover over and view footnotes than other readers, but are less likely to visit the hyperlinked sources in these footnotes. Our findings suggest that WPM readers appear to use links to external sources to verify and authorize Wikipedia content, rather than to examine the sources themselves.

]]>
<![CDATA[Opioids depress breathing through two small brainstem sites]]> https://www.researchpad.co/article/Nc55e8f25-76aa-4f6e-8913-fd72e3a2a88e

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose— opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the µ-Opioid receptor. We find the critical brain site is the preBötzinger Complex, where the breathing rhythm originates, and use genetic tools to reveal that just 70–140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

]]>
<![CDATA[p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle]]> https://www.researchpad.co/article/N0fd6c714-35ca-44ee-8fa3-38e12c178384

The cell cycle regulator p16 is known as a biomarker and an effector of aging. However, its function in intervertebral disc degeneration (IVDD) is unclear. In this study, p16 expression levels were found to be positively correlated with the severity of human IVDD. In a mouse tail suspension (TS)-induced IVDD model, lumbar intervertebral disc height index and matrix protein expression levels were reduced significantly were largely rescued by p16 deletion. In TS mouse discs, reactive oxygen species levels, proportions of senescent cells, and the senescence-associated secretory phenotype (SASP) were all increased, cell cycling was delayed, and expression was downregulated for Sirt1, superoxide dismutase 1/2, cyclin-dependent kinases 4/6, phosphorylated retinoblastoma protein, and transcription factor E2F1/2. However, these effects were rescued by p16 deletion. Our results demonstrate that p16 plays an important role in IVDD pathogenesis and that its deletion attenuates IVDD by promoting cell cycle and inhibiting SASP, cell senescence, and oxidative stress.

]]>
<![CDATA[Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation]]> https://www.researchpad.co/article/N8a2d1f62-2d56-4a51-a836-394c12fd1960

Blood vessels are lined by endothelial cells engaged in distinct organ-specific functions but little is known about their characteristic gene expression profiles. RNA-Sequencing of the brain, lung, and heart endothelial translatome identified specific pathways, transporters and cell-surface markers expressed in the endothelium of each organ, which can be visualized at http://www.rehmanlab.org/ribo. We found that endothelial cells express genes typically found in the surrounding tissues such as synaptic vesicle genes in the brain endothelium and cardiac contractile genes in the heart endothelium. Complementary analysis of endothelial single cell RNA-Seq data identified the molecular signatures shared across the endothelial translatome and single cell transcriptomes. The tissue-specific heterogeneity of the endothelium is maintained during systemic in vivo inflammatory injury as evidenced by the distinct responses to inflammatory stimulation. Our study defines endothelial heterogeneity and plasticity and provides a molecular framework to understand organ-specific vascular disease mechanisms and therapeutic targeting of individual vascular beds.

]]>
<![CDATA[Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis]]> https://www.researchpad.co/article/N0186b1c1-bc1d-4908-9165-e41624455aba

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.

]]>
<![CDATA[Prolonged ovarian storage of mature Drosophila oocytes dramatically increases meiotic spindle instability]]> https://www.researchpad.co/article/Naa9d0b7c-26f2-4d90-bdd1-dc8f454f3378

Human oocytes frequently generate aneuploid embryos that subsequently miscarry. In contrast, Drosophila oocytes from outbred laboratory stocks develop fully regardless of maternal age. Since mature Drosophila oocytes are not extensively stored in the ovary under laboratory conditions like they are in the wild, we developed a system to investigate how storage affects oocyte quality. The developmental capacity of stored mature Drosophila oocytes decays in a precise manner over 14 days at 25°C. These oocytes are transcriptionally inactive and persist using ongoing translation of stored mRNAs. Ribosome profiling revealed a progressive 2.3-fold decline in average translational efficiency during storage that correlates with oocyte functional decay. Although normal bipolar meiotic spindles predominate during the first week, oocytes stored for longer periods increasingly show tripolar, monopolar and other spindle defects, and give rise to embryos that fail to develop due to aneuploidy. Thus, meiotic chromosome segregation in mature Drosophila oocytes is uniquely sensitive to prolonged storage. Our work suggests the chromosome instability of human embryos could be mitigated by reducing the period of time mature human oocytes are stored in the ovary prior to ovulation.

]]>
<![CDATA[Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model]]> https://www.researchpad.co/article/N0bc8fdca-b877-4e98-9222-60231ec07b75

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.

]]>
<![CDATA[Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex]]> https://www.researchpad.co/article/N366fe855-9f7c-4719-8b68-b41f6e4fc286

Occludin (OCLN) mutations cause human microcephaly and cortical malformation. A tight junction component thought absent in neuroepithelium after neural tube closure, OCLN isoform-specific expression extends into corticogenesis. Full-length and truncated isoforms localize to neuroprogenitor centrosomes, but full-length OCLN transiently localizes to plasma membranes while only truncated OCLN continues at centrosomes throughout neurogenesis. Mimicking human mutations, full-length OCLN depletion in mouse and in human CRISPR/Cas9-edited organoids produce early neuronal differentiation, reduced progenitor self-renewal and increased apoptosis. Human neural progenitors were more severely affected, especially outer radial glial cells, which mouse embryonic cortex lacks. Rodent and human mutant progenitors displayed reduced proliferation and prolonged M-phase. OCLN interacted with mitotic spindle regulators, NuMA and RAN, while full-length OCLN loss impaired spindle pole morphology, astral and mitotic microtubule integrity. Thus, early corticogenesis requires full-length OCLN to regulate centrosome organization and dynamics, revealing a novel role for this tight junction protein in early brain development.

]]>
<![CDATA[Induction of Sertoli-like cells from human fibroblasts by NR5A1 and GATA4]]> https://www.researchpad.co/article/N1a043d5e-1d2c-4be8-9df4-c12d76b51d7f

Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). Here, we report the in vitro reprogramming of fibroblasts to human induced Sertoli-like cells (hiSCs). Initially, five transcriptional factors and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles and cellular properties that are similar to those of primary human Sertoli cells. Moreover, hiSCs can sustain the viability of spermatogonia cells harvested from mouse seminiferous tubules. hiSCs suppress the proliferation of human T lymphocytes and protect xenotransplanted human cells in mice with normal immune systems. hiSCs also allow us to determine a gene associated with Sertoli cell only syndrome (SCO), CX43, is indeed important in regulating the maturation of Sertoli cells.

]]>