Successful Biomaterial-Based Artificial Organ—Updates on Artificial Blood Vessels

International audienceIn the perfect world—an ideal laboratory grown vascular graft must be composed of viable tissue elements with potentials for repair and regeneration, an acceptable range of resistance to thrombosis—infections, sensitivity to vasoactive mediators, secretory and contractile properties, mimicking natural blood vessels. Three key components of generating such custom-made vessels are biocompatible polymer of natural structural proteins for building a scaffold, healthy primary vascular cells grown in the scaffold maintaining close anatomical and functional integrity, and provision for a microenvironment for providing balanced metabolic support. In addition, maintenance of a pulsatile flow of nutrients and polarization of cellular components in the synthetic vessels are also important. Obtaining decellularized vascular grafts from cadaveric donors or xenografts, populating with recipient’s primary vascular cells, and maintaining them in bioreactors or recipients own body tissue are other potential alternative approaches. Here, we will discuss some central aspects and updated information on authentic artificial blood vessel

The Interplay between Finasteride-Induced Androgen Imbalance, Endoplasmic Reticulum Stress, Oxidative Stress, and Liver Disorders in Paternal and Filial Generation

Finasteride (Fin) causes androgen imbalance by inhibiting the conversion of testosterone (T) to its more active metabolite, dihydrotestosterone (DHT). Androgen receptors (AR) are present (e.g., in hepatocytes), which have well-developed endoplasmic reticulum (ERet). Cellular protein quality control is carried out by ERet in two paths: (i) unfolded protein response (UPR) and/or (ii) endoplasmic reticulum associated degradation (ERAD). ERet under continuous stress can generate changes in the UPR and can direct the cell on the pathway of life or death. It has been demonstrated that genes involved in ERet stress are among the genes controlled by androgens in some tissues. Oxidative stress is also one of the factors affecting the functions of ERet and androgens are one of the regulators of antioxidant enzyme activity. In this paper, we discuss/analyze a possible relationship between androgen imbalance in paternal generation with ERet stress and liver disorders in both paternal and filial generation. In our rat model, hyperglycemia and subsequent higher accumulation of hepatic glycogen were observed in all filial generation obtained from females fertilized by Fin-treated males (F1:Fin). Importantly, genes encoding enzymes involved in glucose and glycogen metabolism have been previously recognized among UPR targets

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

Complement Activation Products in Patients with Chronic Schizophrenia

Evidence suggests a role of the immune system in the pathogenesis of a number of mental conditions, including schizophrenia (SCH). In terms of physiology, aside from its crucial protective function, the complement cascade (CC) is a critical element of the regeneration processes, including neurogenesis. Few studies have attempted to define the function of the CC components in SCH. To shed more light on this topic, we compared the levels of complement activation products (CAP) (C3a, C5a and C5b-9) in the peripheral blood of 62 patients with chronic SCH and disease duration of ≥ 10 years with 25 healthy controls matched for age, sex, BMI and smoking status. Concentrations of all the investigated CAP were elevated in SCH patients. However, after controlling for potential confounding factors, significant correlations were observed between SCH and C3a (M = 724.98 ng/mL) and C5a (M = 6.06 ng/mL) levels. In addition, multivariate logistic regression showed that C3a and C5b-9 were significant predictors of SCH. There were no significant correlations between any CAP and SCH symptom severity or general psychopathology in SCH patients. However, two significant links emerged between C3a and C5b-9 and global functioning. Increased levels of both complement activation products in the patient group as compared to healthy controls raise questions concerning the role of the CC in the etiology of SCH and further demonstrate dysregulation of the immune system in SCH patients

Psychopathology and Stem Cell Mobilization in Ultra-High Risk of Psychosis and First-Episode Psychosis Patients

Although regenerative and inflammatory processes are involved in the etiopathogenesis of many psychiatric disorders, their roles are poorly understood. We investigate the potential role of stem cells (SC) and factors influencing the trafficking thereof, such as complement cascade (CC) components, phospholipid substrates, and chemokines, in the etiology of schizophrenia. We measured sphingosine-1-phosphate (S1P), stromal-derived factor 1 (SDF-1), and CC cleavage fragments (C3a, C5a, and C5b-C9; also known as the membrane attack complex) in the peripheral blood of 49 unrelated patients: 9 patients with ultra-high risk of psychosis (UHR), 22 patients with first-episode psychosis (FEP), and 18 healthy controls (HC). When compared with the HC group, the UHR and FEP groups had higher levels of C3a. We found no significant differences in hematopoietic SC, very small embryonic-like stem cell (VSEL), C5a, S1P, or SDF-1 levels in the UHR and FEP groups. However, among FEP patients, there was a significant positive correlation between VSELs (CD133+) and negative symptoms. These preliminary findings support the role of the immune system and regenerative processes in the etiology of schizophrenia. To establish the relevance of SC and other factors affecting the trafficking thereof as potential biomarkers of schizophrenia, more studies on larger groups of individuals from across the disease spectrum are needed