Maternal obesity and placental function: impaired maternal-fetal axis.

The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.

KIF2C/MCAK a prognostic biomarker and its oncogenic potential in malignant progression, and prognosis of cancer patients: a systematic review and meta-analysis as biomarker.

KIF2C/MCAK (KIF2C) is the most well-characterized member of the kinesin-13 family, which is critical in the regulation of microtubule (MT) dynamics during mitosis, as well as interphase. This systematic review briefly describes the important structural elements of KIF2C, its regulation by multiple molecular mechanisms, and its broad cellular functions. Furthermore, it systematically summarizes its oncogenic potential in malignant progression and performs a meta-analysis of its prognostic value in cancer patients. KIF2C was shown to be involved in multiple crucial cellular processes including cell migration and invasion, DNA repair, senescence induction and immune modulation, which are all known to be critical during the development of malignant tumors. Indeed, an increasing number of publications indicate that KIF2C is aberrantly expressed in multiple cancer entities. Consequently, we have highlighted its involvement in at least five hallmarks of cancer, namely: genome instability, resisting cell death, activating invasion and metastasis, avoiding immune destruction and cellular senescence. This was followed by a systematic search of KIF2C/MCAK's expression in various malignant tumor entities and its correlation with clinicopathologic features. Available data were pooled into multiple weighted meta-analyses for the correlation between KIF2Chigh protein or gene expression and the overall survival in breast cancer, non-small cell lung cancer and hepatocellular carcinoma patients. Furthermore, high expression of KIF2C was correlated to disease-free survival of hepatocellular carcinoma. All meta-analyses showed poor prognosis for cancer patients with KIF2Chigh expression, associated with a decreased overall survival and reduced disease-free survival, indicating KIF2C's oncogenic potential in malignant progression and as a prognostic marker. This work delineated the promising research perspective of KIF2C with modern in vivo and in vitro technologies to further decipher the function of KIF2C in malignant tumor development and progression. This might help to establish KIF2C as a biomarker for the diagnosis or evaluation of at least three cancer entities.

ZTBus: A Large Dataset of Time-Resolved City Bus Driving Missions.

This paper presents the Zurich Transit Bus (ZTBus) dataset, which consists of data recorded during driving missions of electric city buses in Zurich, Switzerland. The data was collected over several years on two trolley buses as part of multiple research projects. It involves more than a thousand missions across all seasons, each mission usually covering a full day of operation. The ZTBus dataset contains detailed information on the vehicle's power demand, propulsion system, odometry, global position, ambient temperature, door openings, number of passengers, dispatch patterns within the public transportation network, etc. All signals are synchronized in time and include an absolute timestamp in tabular form. The dataset can be used as a foundation for a variety of studies and analyses. For example, the data can serve as a basis for simulations to estimate the performance of different public transit vehicle types, or to evaluate and optimize control strategies of hybrid electric vehicles. Furthermore, numerous influencing factors on vehicle operation, such as traffic, passenger volume, etc., can be analyzed in detail.

Finding an effective MRI sequence to visualise the electroporated area in plant-based models by quantitative mapping.

Plant-based models can reduce the number of animal studies for electroporation research in medical cancer treatment modalities like irreversible electroporation. Magnetic resonance imaging (MRI) provides volumetric visualisation of electroporated animal or plant tissues; however, contrast behaviour is complex, depending on tissue and sequence parameters. This study numerically analysed contrast between electroporated and non-electroporated tissue at 1.5 T in various MRI sequences (DWI, T1W, T2W, T2*W, PDW, FLAIR) performed 4 h after electroporation in apples (N = 4) and potatoes (N = 8). Sequence parameters (inversion time [TI], echo time [TE], b-value) for optimal contrast and electroporation-mediated changes in T1 and T2 relaxation times and apparent diffusion coefficient (ADC) were determined for potato (N = 4) using quantitative parameter mapping. FLAIR showed the electroporated zone in potatoes with best contrast, whereas no sequence yielded clear visibility in apples. After electroporation, T1 and T2 in potato decreased by 29% ([1245 ± 54 to 886 ± 119] ms) and 12% ([249 ± 17 to 217 ± 12] ms), respectively. ADC increased by 11% ([1303 ± 25 to 1449 ± 28] × 10-6 mm2/s). Optimal contrast was found for TI = 1000 ms, low TE and high b-value. T1 was most sensitive to EP-mediated tissue changes. Future research could use this methodology and findings to obtain high-contrast MR images of electroporated and non-electroporated biological tissues.

Plant-based model for the visual evaluation of electroporated area after irreversible electroporation and its comparison to in-vivo animal data.

Electroporation (EP) is widely used in medicine, such as cancer treatment, in form of electrochemotherapy or irreversible electroporation (IRE). For EP device testing, living cells or tissue inside a living organism (including animals) are needed. Plant-based models seem to be a promising alternative to substitute animal models in research. The aim of this study is to find a suitable plant-based model for visual evaluation of IRE, and to compare the geometry of electroporated areas with in-vivo animal data.For this purpose, a variety of fruit and vegetables were selected and visually evaluated after 0/1/2/4/6/8/12/16/24 h post-EP. Apple and potato were found to be suitable models as they enabled a visual evaluation of the electroporated area. For these models, the size of the electroporated area was determined after 0/1/2/4/6/8/12/16/24 h. For apples, a well-defined electroporated area was visual within two hours, while in potatoes it reached a plateau after eight hours only. The electroporated area of apple, which showed the fastest visual results was then compared to a retrospectively evaluated swine liver IRE dataset which had been obtained for similar conditions. The electroporated area of the apple and swine liver both showed a spherical geometry of comparable size. For all experiments, the standard protocol for human liver IRE was followed. To conclude, potato and apple were found to be suitable plant-based models for the visual evaluation of electroporated area after irreversible EP, with apple being the best choice for fast visual results. Given the comparable range, the size of the electroporated area of the apple may be promising as a quantitative predictor in animal tissue. Even if plant-based models cannot completely replace animal experiments, they can be used in the early stages of EP device development and testing, decreasing animal experiments to the necessary minimum.

Cancer-educated mammary adipose tissue-derived stromal/stem cells in obesity and breast cancer: spatial regulation and function.

BACKGROUND: Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Breast adipose tissue-derived mesenchymal stromal/stem cells (bASCs) are crucial components of the tumor microenvironment. A key step initially involved in this process might be the de-differentiation of bASCs into tumor supporting phenotypes. METHODS: In the present work, we isolated bASCs from adipose tissues adjacent to the tumor (aT bASCs) from lean- (ln-aT bASCs, BMI ≤ 25) and breast cancer patients with obesity (ob-aT bASCs, BMI ≥ 35), and analyzed their phenotypes with functional assays and RNA sequencing, compared to their counterparts isolated from adipose tissues distant from the tumor (dT bASCs). RESULTS: We show that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological differentiation capacity, and upregulate metastasis-promoting factors. While ln-aT bASCs stimulate proliferation, motility and chemoresistance by inducing epithelial-mesenchymal transition of low malignant breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant breast cancer cells. CONCLUSION: Breast cancer-associated bASCs are able to foster malignancy of breast cancer cells by multiple mechanisms, especially, induction of epithelial-mesenchymal transition and activation of stemness-associated genes in breast cancer cells. Blocking the de-differentiation of bASCs in the tumor microenvironment could be a novel strategy to develop an effective intervention for breast cancer patients. SIGNIFICANCE: This study provides mechanistic insights into how obesity affects the phenotype of bASCs in the TME. Moreover, it highlights the molecular changes inside breast cancer cells upon cell-cell interaction with cancer-educated bASCs.

Global sensitivity study for irreversible electroporation: Towards treatment planning under uncertainty.

BACKGROUND: Electroporation-based cancer treatments are minimally invasive, nonthermal interventional techniques that leverage cell permeabilization to ablate the target tumor. However, the amount of permeabilization is susceptible to the numerous uncertainties during treatment, such as patient-specific variations in the tissue, type of the tumor, and the resolution of imaging equipment. These uncertainties can reduce the extent of ablation in the tissue, thereby affecting the effectiveness of the treatment. PURPOSE: The aim of this work is to understand the effect of these treatment uncertainties on the treatment outcome for irreversible electroporation (IRE) in the case of colorectal liver metastasis (CRLM). Understanding the nature and extent of these effects can help us identify the influential treatment parameters and build better models for predicting the treatment outcome. METHODS: This is an in silico study using a static computational model with a custom applicator design, spherical tissue, and tumor geometry. A nonlinear electrical conductivity, dependent on the local electric field, is considered. Morris analysis is used to identify the influential treatment parameters on the treatment outcome. Seven treatment parameters pertaining to the relative tumor location with respect to the applicator, the tumor growth pattern, and the electrical conductivity of tissue are analyzed. The treatment outcome is measured in terms of the relative tumor ablation with respect to the target ablation volume and total ablation volume. RESULTS: The Morris analysis was performed with 800 model evaluations, sampled from the seven dimensional input parameter space. Electrical properties of the tissue, especially the electrical conductivity of the tumor before ablation, were found to be the most influential parameter for relative tumor ablation and total ablation volume. This parameter was found to be about 4-15 times more influential than the least influential parameter, depending on the tumor size. The tumor border configuration was identified as the least important parameter for treatment effectiveness. The most desired treatment outcome is obtained by a combination of high healthy liver conductivity and low tumor conductivity. This information can be used to tackle worst-case scenarios in treatment planning. Finally, when the safety margins used in the clinical applications are accounted for, the effects of uncertainties in the treatment parameters reduce drastically. CONCLUSIONS: The results of this work can be used to create an efficient surrogate estimator for uncertainty quantification in the treatment outcome, that can be utilized in optimal real-time treatment planning solutions.

Microtubule Dynamics and Cancer.

Microtubules (MTs) are highly dynamic key components of the cytoskeleton composed of alpha- and beta-tubulin heterodimers [...].

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer.

Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell-cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial-mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.

Possible Alterations of Imaging Patterns in Computed Tomography for Delta-VOC of SARS-CoV-2.

BACKGROUND: So far, typical findings for COVID-19 in computed tomography (CT) have been described as bilateral, multifocal ground glass opacities (GGOs) and consolidations, as well as intralobular and interlobular septal thickening. On the contrary, round consolidations with the halo sign are considered uncommon and are typically found in fungal infections, such as invasive pulmonary aspergillosis. The authors recently observed several patients with COVID-19 pneumonia presenting with round, multifocal consolidations accompanied by a halo sign. As this may indicate alterations of CT morphology based on the virus variant, the aim of this study was to investigate this matter in more detail. METHODS: 161 CT scans of patients with confirmed SARS-CoV-2 infection (RT-PCR within 2 days of CT) examined between January 2021 and September 15, 2021 were included. Follow-up examinations, patients with invasive ventilation at the time of CT, and patients with insufficient virus typing for variants of concern (VOC) were excluded. CT scans were assessed for vertical and axial distribution of pulmonary patterns, degree of involvement, uni- vs. bilaterality, reticulations, and other common findings. The mean density of representative lesions was assessed in Hounsfield units. Results were compared using Mann-Whitney U-tests, Student's t-rests, descriptive statistics, and Fisher's exact tests. RESULTS: 75 patients did not meet the inclusion criteria. Therefore, 86/161 CT scans of unique patients were analyzed. PCR VOC testing confirmed manifestation of the Delta-VOC SARS-CoV-2 in 22 patients, 39 patients with Alpha-VOC and the remaining 25 patients with Non-VOC SARS-CoV-2 infections. Three patients with the Delta-VOC demonstrated multiple pulmonary masses or nodules with surrounding halo sign, whereas no patients with either Alpha-VOC (p = 0.043) or non-VOC (p = 0.095) demonstrated these findings. All three patients were admitted to normal wards and had no suspicion of a pulmonary co-infection. Patients with Delta-VOC were less likely to have ground glass opacities compared to Alpha-VOC (7/22 or 31.8 % vs. 4/39 or 10.3 %; p < 0.001), whereas a significant difference has not been observed between Delta-VOC and non-VOC (5/25 or 20 %; p = 0.348). The mean representative density of lesions did not show significant differences between the studied cohorts. CONCLUSION: In this study 3 out of 22 patients (13.6 %) with Delta-VOC presented with bilateral round pulmonary masses or nodules with surrounding halo signs, which has not been established as a notable imaging pattern in COVID-19 pneumonia yet. Compared to the other cohorts, a lesser percentage of patients with Delta-VOC presented with ground glass opacities. Based on these results Delta-VOC might cause a divergence in CT-morphologic phenotype. KEY POINTS: · Until recently, CT-morphologic signs of COVID-19 pneumonia have been presumed to be uncontroversially understood. Yet, recently the authors observed diverging pulmonary alterations in patients infected with Delta-VOC.. · These imaging alterations included round pulmonary masses or nodules with surrounding halo sign.. · These imaging alterations have not yet been established as typical for COVID-19 pneumonia, yet.. · Based on these results, Delta-VOC could impose a divergence of CT-morphologic phenotype.. CITATION FORMAT: · Yüksel C, Sähn M, Kleines M et al. Possible Alterations of Imaging Patterns in Computed Tomography for Delta-VOC of SARS-CoV-2 . Fortschr Röntgenstr 2022; 194: 1229 - 1241.

BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis.

BACKGROUND: The key oncogene B-cell lymphoma 6 (BCL6) drives malignant progression by promoting proliferation, overriding DNA damage checkpoints and blocking cell terminal differentiation. However, its functions in the placenta and the endometrium remain to be defined. OBJECTIVE AND RATIONALE: Recent studies provide evidence that BCL6 may play various roles in the human placenta and the endometrium. Deregulated BCL6 might be related to the pathogenesis of pre-eclampsia (PE) as well as endometriosis. In this narrative review, we aimed to summarize the current knowledge regarding the pathophysiological role of BCL6 in these two reproductive organs, discuss related molecular mechanisms, and underline associated research perspectives. SEARCH METHODS: We conducted a comprehensive literature search using PubMed for human, animal and cellular studies published until October 2021 in the following areas: BCL6 in the placenta, in PE and in endometriosis, in combination with its functions in proliferation, fusion, migration, invasion, differentiation, stem/progenitor cell maintenance and lineage commitment. OUTCOMES: The data demonstrate that BCL6 is important in cell proliferation, survival, differentiation, migration and invasion of trophoblastic cells. BCL6 may have critical roles in stem/progenitor cell survival and differentiation in the placenta and the endometrium. BCL6 is aberrantly upregulated in pre-eclamptic placentas and endometriotic lesions through various mechanisms, including changes in gene transcription and mRNA translation as well as post-transcriptional/translational modifications. Importantly, increased endometrial BCL6 is considered to be a non-invasive diagnostic marker for endometriosis and a predictor for poor outcomes of IVF. These data highlight that BCL6 is crucial for placental development and endometrium homeostasis, and its upregulation is associated with the pathogenesis of PE, endometriosis and infertility. WIDER IMPLICATIONS: The lesson learned from studies of the key oncogene BCL6 reinforces the notion that numerous signaling pathways and regulators are shared by tumors and reproductive organs. Their alteration may promote the progression of malignancies as well as the development of gestational and reproductive disorders.

Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia.

BACKGROUND: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities. METHODS: In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student's t test (two-tailed and paired or homoscedastic) or an unpaired Mann-Whitney U test (two-tailed). RESULTS: The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs' proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation. CONCLUSIONS: These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.

Mitotic Centromere-Associated Kinesin (MCAK/KIF2C) Regulates Cell Migration and Invasion by Modulating Microtubule Dynamics and Focal Adhesion Turnover.

The microtubule (MT) cytoskeleton is crucial for cell motility and migration by regulating multiple cellular activities such as transport and endocytosis of key components of focal adhesions (FA). The kinesin-13 family is important in the regulation of MT dynamics and the best characterized member of this family is the mitotic centromere-associated kinesin (MCAK/KIF2C). Interestingly, its overexpression has been reported to be related to increased metastasis in various tumor entities. Moreover, MCAK is involved in the migration and invasion behavior of various cell types. However, the precise molecular mechanisms were not completely clarified. To address these issues, we generated CRISPR/dCas9 HeLa and retinal pigment epithelium (RPE) cell lines overexpressing or downregulating MCAK. Both up- or downregulation of MCAK led to reduced cell motility and poor migration in malignant as well as benign cells. Specifically, it's up- or downregulation impaired FA protein composition and phosphorylation status, interfered with a proper spindle and chromosome segregation, disturbed the assembly and disassembly rate of FA, delayed cell adhesion, and compromised the plus-tip dynamics of MTs. In conclusion, our data suggest MCAK act as an important regulator for cell motility and migration by affecting the actin-MT cytoskeleton dynamics and the FA turnover, providing molecular mechanisms by which deregulated MCAK could promote malignant progression and metastasis of tumor cells.

The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery.

Primary Cilia in Trophoblastic Cells: Potential Involvement in Preeclampsia.

The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics.

The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.

A Message from the Human Placenta: Structural and Immunomodulatory Defense against SARS-CoV-2.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage, and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.

RITA Is Expressed in Trophoblastic Cells and Is Involved in Differentiation Processes of the Placenta.

Preeclampsia (PE) remains a leading cause of maternal and perinatal mortality and morbidity worldwide. Its pathogenesis has not been fully elucidated and no causal therapy is currently available. It is of clinical relevance to decipher novel molecular biomarkers. RITA (RBP-J (recombination signal binding protein J)-interacting and tubulin-associated protein) has been identified as a negative modulator of the Notch pathway and as a microtubule-associated protein important for cell migration and invasion. In the present work, we have systematically studied RITA's expression in primary placental tissues from patients with early- and late-onset PE as well as in various trophoblastic cell lines. RITA is expressed in primary placental tissues throughout gestation, especially in proliferative villous cytotrophoblasts, in the terminally differentiated syncytiotrophoblast, and in migrating extravillous trophoblasts. RITA's messenger RNA (mRNA) level is decreased in primary tissue samples from early-onset PE patients. The deficiency of RITA impairs the motility and invasion capacity of trophoblastic cell lines, and compromises the fusion ability of trophoblast-derived choriocarcinoma cells. These data suggest that RITA may play important roles in the development of the placenta and possibly in the pathogenesis of PE.

Subcutaneous and Visceral Adipose-Derived Mesenchymal Stem Cells: Commonality and Diversity.

Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.

Restoration of primary cilia in obese adipose-derived mesenchymal stem cells by inhibiting Aurora A or extracellular signal-regulated kinase.

BACKGROUND: Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). ASCs are indispensable for tissue homeostasis/repair, immunomodulation, and cell renewal. It has been demonstrated that obese ASCs are defective in differentiation, motility, immunomodulation, and replication. We have recently reported that some of these defects are linked to impaired primary cilia, which are unable to properly convey and coordinate a variety of signaling pathways. We hypothesized that the rescue of the primary cilium in obese ASCs would restore their functional properties. METHODS: Obese ASCs derived from subcutaneous and visceral adipose tissues were treated with a specific inhibitor against Aurora A or with an inhibitor against extracellular signal-regulated kinase 1/2 (Erk1/2). Multiple molecular and cellular assays were performed to analyze the altered functionalities and their involved pathways. RESULTS: The treatment with low doses of these inhibitors extended the length of the primary cilium, restored the invasion and migration potential, and improved the differentiation capacity of obese ASCs. Associated with enhanced differentiation ability, the cells displayed an increased expression of self-renewal/stemness-related genes like SOX2, OCT4, and NANOG, mediated by reduced active glycogen synthase kinase 3 ß (GSK3ß). CONCLUSION: This work describes a novel phenomenon whereby the primary cilium of obese ASCs is rescuable by the low-dose inhibition of Aurora A or Erk1/2, restoring functional ASCs with increased stemness. These cells might be able to improve tissue homeostasis in obese patients and thereby ameliorate obesity-associated diseases. Additionally, these functionally restored obese ASCs could be useful for novel autologous mesenchymal stem cell-based therapies.