Bone Marrow-Derived VSELs Engraft as Lung Epithelial Progenitor Cells after Bleomycin-Induced Lung Injury.

BACKGROUND: Alveolar type 2 (AT2) cells and bronchioalveolar stem cells (BASC) perform critical regenerative functions in response to lung damage. Published data show that nonhematopoietic, bone marrow-derived "very small embryonic-like stem cells" (VSELs) can differentiate in vivo into surfactant protein C (SPC)-producing AT2 cells in the lung. Here, we test directly whether VSEL-derived BASC and AT2 cells function to produce differentiated progeny. METHODS: using a reporter mouse in which the H2B-GFP fusion protein is driven from the murine SPC promoter, we tested whether bone marrow-derived VSELs or non-VSEL/nonhematopoietic stem cells (non-VSEL/non-HSCs) can differentiate into AT2 and BASC cells that function as progenitor cells. Immediately following bleomycin administration, WT recipient mice underwent intravenous administration of VSELs or non-VSEL/non-HSCs from SPC H2B-GFP mice. GFP+ AT2 and BASC were isolated and tested for progenitor activity using in vitro organoid assays. RESULTS: after 21 days in vivo, we observed differentiation of VSELs but not non-VSEL/non-HSCs into phenotypic AT2 and BASC consistent with previous data in irradiated recipients. Subsequent in vitro organoid assays revealed that VSEL-derived AT2 and BASC maintained physiological potential for differentiation and self-renewal. CONCLUSION: these findings prove that VSELs produce functional BASC and AT2 cells, and this may open new avenues using VSELs to develop effective cell therapy approaches for patients with lung injury.

The potential association between a new angiogenic marker fractalkine and a placental vascularization in preeclampsia.

PURPOSE: Impaired angiogenesis is one of the most common findings in preeclamptic placentas. A new angiogenetic role of fractalkine (CX3CL1) is recently recognized apart from inflammatory activity. In this study, a link between CX3CL1 and the development of placental vasculature in preeclampsia was examined. METHODS: The study comprised 52 women allocated to Group 1 (normotensive, n = 23) and Group 2 (preeclampsia, n = 29). In each group Doppler parameters, serum levels of CX3CL1, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) were assessed between 30 and 32 week of pregnancy. After the delivery, placental samples were taken and the vascularization and expression of CX3CR1 receptor were assessed after immunostaining. RESULTS: CX3CL1 and sFlt-1 serum levels were significantly higher levels in Group 2 vs Group 1, while PlGF serum levels was significantly lower in Group 2. Lower cerebroplacental ratio (CPR) was observed in Group 2. The vascular/extravascular tissue index (V/EVTI) was significantly lower in Group 2, while compared to Group 1, with the lowest value in the fetus growth restriction (FGR) subgroup (0.18 ± 0.02; 0.24 ± 0.03; 0.16 ± 0.02, respectively). The expression of examined CX3CR1 was higher in Group 2, while compared to Group 1, reaching the highest values in FGR subgroup. There was a moderate negative correlation between birth weight, V/EVTI and CX3CL1 serum level and CX3CR1 placental expression in the group of pregnancies complicated with preeclampsia. CONCLUSION: The significant underdevelopment of placental vascular network in preeclampsia is associated with the change in the CX3CL1/CX3CR1 system, especially in FGR complicated pregnancies.

Corrigendum to "Comparative Analysis of the Occurrence and Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Hemophilic Arthropathy and Osteoarthritis".

[This corrects the article DOI: 10.1155/2020/2932696.].

Comparative Analysis of the Occurrence and Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Hemophilic Arthropathy and Osteoarthritis.

OBJECTIVE: Hemophilic arthropathy is characterized by recurrent bleeding episodes in patients with hemophilia leading to irreversible joint degeneration. The involvement of CX3CL1 (fractalkine) and its receptor CX3CR1 was observed in the pathogenesis of numerous arthritis-associated diseases. Taking this into account, we have presented a study investigating the role of the CX3CL1/CX3XR1 axis in the course of hemophilic arthropathy, including the CX3CL1-dependent expression of CD56+, CD68+, and CD31+ cells along with evaluation of articular cartilage and synovial membrane morphology. METHODS: The study was carried out using cases (n = 20) of end-stage hemophilic arthropathy with a severe type of hemophilia A and control cases (n = 20) diagnosed with osteoarthritis. The biofluids including blood serum and synovial fluid were obtained intraoperatively for the evaluation of CX3CL1 using the ELISA test. Tissue specimens including articular cartilage and synovial membrane were similarly collected during surgery and stained immunohistologically using selected antibodies including anti-CX3CR1, anti-CD56, anti-CD68, and anti-CD31. Additionally, the analysis included the assessment of articular cartilage, synovial membrane, and blood vessel morphology. RESULTS: In our study, we have documented increased average concentration of CX3CL1 in the blood serum of the study group (7.16 ± 0.53 ng/ml) compared to the control group (5.85 ± 0.70 ng/ml) without statistically significant difference in synovial fluid concentration at the same time. We have observed an increased macrophage presence with more marked proliferation and fibrosis of the synovial membrane in the study group. Remaining results such as expression of CX3CR1 presence of NK cells and larger surface area of blood vessels within the synovial membrane were noted also without statistical significance. CONCLUSIONS: This study has demonstrated collective CX3CL1/CX3CR1 axis involvement in hemophilic arthropathy pathogenesis introducing new interesting diagnostics and a therapeutic target.

Can adipokine visfatin be a novel marker of pregnancy-related disorders in women with obesity?

Overweight and obesity have become a dangerous disease requiring multiple interventions, treatment and preventions. In women of reproductive age, obesity is one of the most common medical conditions. Among others, obese state is characterized by low-grade systemic inflammation and enhanced oxidative stress. Increased maternal body mass index might amplify inflammation and reactive oxygen species production, which is associated with unfavourable clinical outcomes that affect both mother and child. Intrauterine growth retardation, preeclampsia, or gestational diabetes mellitus are examples of the hampered maternal and foetoplacental unit interactions. Visfatin is the obesity-related adipokine produced mainly by the visceral adipose tissue. Visfatin affects glucose homeostasis, as well as the regulation of genes related to oxidative stress and inflammatory response. Here, we review visfatin interactions in pregnancy-related disorders linked to obesity. We highlight the possible predictive and prognostic value of visfatin in diagnostic strategies on gravidas with obesity.

Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood.

We found that circadian changes in ATP level in peripheral blood (PB) activate the Nlrp3 inflammasome, which triggers diurnal release of hematopoietic stem/progenitor cells (HSPCs) from murine bone marrow (BM) into PB. Consistent with this finding, we observed circadian changes in expression of mRNA for Nlrp3 inflammasome-related genes, including Nlrp3, caspase 1, IL-1ß, IL-18, gasdermin (GSDMD), HMGB1, and S100A9. Circadian release of HSPCs from BM into PB as well as expression of Nlrp3-associated genes was decreased in mice in which pannexin 1-mediated secretion of ATP was inhibited by the blocking peptide 10Panx and in animals exposed to the specific small-molecule inhibitor of the Nlrp3 inflammasome MCC950. In addition to HSPCs, a similar decrease in diurnal cell counts was observed for mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). These results shed more light on the complexity of circadian regulation of HSPC release into PB, which is coordinated in a purinergic signaling-, innate immunity-dependent manner. Moreover, in addition to circadian changes in expression of the Nlrp3 inflammasome we also observed diurnal changes in expression of other inflammasomes, including Aim2, Nrp1a, and Nlrp1b.

Fractalkine and placental growth factor: A duet of inflammation and angiogenesis in cardiovascular disorders.

Inflammation and angiogenesis are two interdependent processes underlying pathogenesis of cardiovascular disorders. The initiation and progression of atherosclerosis strongly depends on specific patterns of cytokine expression. In this review, we analyze correlation between expression of two members of the cytokine family and the processes of inflammation and angiogenesis related to atherosclerosis. Placental growth factor and chemokine CX3XL1 (fractalkine) promote inflammatory cell infiltration, angiogenesis and plaque rupture. Because these cytokines share similar roles during atherosclerotic development, their combined value as a predictor or indicator of inflammation and vascular healing may be extremely useful.

Sirtuins, epigenetics and longevity.

Aging of organisms begins from a single cell at the molecular level. It includes changes related to telomere shortening, cell senescence and epigenetic modifications. These processes accumulate over the lifespan. Research studies show that epigenetic signaling contributes to human disease, tumorigenesis and aging. Epigenetic DNA modifications involve changes in the gene activity but not in the DNA sequence. An epigenome consists of chemical modifications to the DNA and histone proteins without the changes in the DNA sequence. These modifications strongly depend on the environment, could be reversible and are potentially transmittable to daughter cells. Epigenetics includes DNA methylation, noncoding RNA interference, and modifications of histone proteins. Sirtuins, a family of nicotine adenine dinucleotide (NAD+)-dependent enzymes, are involved in the cell metabolism and can regulate many cellular functions including DNA repair, inflammatory response, cell cycle or apoptosis. Literature shows the strong interconnection between sirtuin expression and aging processes. However, the direct relationship is still unknown. Here, we would like to summarize the existing knowledge about epigenetic processes in aging, especially those related to sirtuin expression. Another objective is to explain why some negative correlations between sirtuin activity and the rate of aging can be assumed.

The Molecular Influence of Graphene and Graphene Oxide on the Immune System Under In Vitro and In Vivo Conditions.

Graphene and graphene oxide (GO), due to their physicochemical properties and biocompatibility, can be used as an innovative biomedical material in biodetection, drug distribution in the body, treating neoplasms, regenerative medicine, and in implant surgery. Research on the biomedical use of graphene and GO that has been carried out until now is very promising and shows that carbon nanomaterials present high biocompatibility. However, the intolerance of the immune system to graphene nanomaterials, however low, may in consequence make it impossible to use them in medicine. This paper shows the specific mechanism of the molecular influence of graphene and GO on macrophages and lymphocytes under in vitro and in vivo conditions and their practical application in medicine. Under in vitro conditions graphene and GO cause an increased production of pro-inflammatory cytokines, mainly IL-1, IL-6, IL-10 and TNF-α, as a result of the activation of Toll-like receptors in macrophages. Graphene activates apoptosis in macrophages through the TGFbr/Smad/Bcl-2 pathway and also through JNK kinases that are stimulated by an increase of ROS in the cell or through a signal received by Smad proteins. Under in vivo conditions, graphene nanomaterials induce the development of the local inflammatory reaction and the development of granulomas in parenchymal organs. However, there is a huge discrepancy between the results obtained by different research groups, which requires a detailed analysis. In this work we decided to collect and analyze existing research and tried to explain the discrepancies. Understanding the precise mechanism of how this nanomaterial influences immune system cells allows estimating the potential influence of grapheme and GO on the human body.

Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells.

Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines.

Apigenin inhibits TGF-ß1 induced fibroblast-to-myofibroblast transition in human lung fibroblast populations.

BACKGROUND: Flavonoids are dietary plant compounds suspected to reduce the incidence of chronic diseases in several regions of the world. Due to anti-allergic and anti-inflammatory activities, apigenin (4',5,7,-trihydroxyflavone) is thought to interfere with crucial events in the pathomechanism of asthma. However, the effect of apigenin on TGF-ß-induced fibroblast-to-myofibroblast transition (FMT) in human lung fibroblast populations, a key event in asthma progression, has not yet been addressed. METHODS: Primary human bronchial fibroblasts (HBFs) propagated from ex vivo bronchial biopsies derived from patients with diagnosed asthma and human embryonic lung IMR-90 fibroblasts were cultured in vitro and treated with TGF-ß1 and apigenin. The myofibroblast fraction in fibroblast populations was evaluated by immunocytochemistry. Expression of α-smooth muscle actin (α-SMA) and tenascin C were assessed at the mRNA and protein level by real-time RT-PCR and immunoblotting, respectively. Additionally, proliferation and viability tests and time lapse-monitoring of movement of individual HBFs and IMR-90 cells were evaluated. RESULTS: We show that apigenin attenuates TGF-ß1-induced FMT in cultures of HBFs, and the magnitude of this attenuation was found to be similar to that observed in the established cell line of lung IMR-90 fibroblasts. Notably, FMT inhibition was observed at low (≈10 µM), non-cytotoxic and non-cytostatic apigenin concentrations and could be correlated with the inhibition of α-SMA and tenascin C expression in HBFs at the mRNA level. CONCLUSIONS: Our data are the first to demonstrate that apigenin inhibits the TGF-ß1-induced expansion of hyper-contractile, α-smooth muscle actin - positive myofibroblasts within populations of HBFs derived from asthmatic patients. They also indicate the possible interference of apigenin with bronchial wall remodeling during the asthmatic process in vivo.