HSF-1 enhances cardioprotective potential of stem cells via exosome biogenesis and their miRNA cargo enrichment.

Stem cell therapy provides a hope to no option heart disease patient group. Stem cells work via different mechanisms of which paracrine mechanism is reported to justify most of the effects. Therefore, identifying the control arms for paracrine cocktail production is necessary to tailor stem cell functions in disease contextual manner. In this study, we describe a novel paracrine cocktail regulatory axis, in stem cells, to enhance their cardioprotective abilities. We identified that HSF1 knockout resulted in reduced cardiac regenerative abilities of mesenchymal stem cells (MSCs) while its overexpression had opposite effects. Altered exosome biognesis and their miRNA cargo enrichment were found to be underlying these altered regenerative abilities. Decreased production of exosomes by MSCs accompanied their loss of HSF1 and vice versa. Moreover, the exosomes derived from HSF1 depleted MSCs showed significantly reduced candidate miRNA expression (miR-145, miR-146, 199-3p, 199b and miR-590) compared to those obtained from HSF1 overexpressing MSCs. We further discovered that HSF1 mediates miRNAs' enrichment into exosomes via Y binding protein 1 (YBX1) and showed, by loss and gain of function strategies, that miRNAs' enrichment in mesenchymal stem cell derived exosomes is deregulated with altered YBX1 expression. It was finally demonstrated that absence of YBX1 in MSCs, with normal HSF1 expression, resulted in significant accumulation of candidate miRNAs into the cells. Together, our data shows that HSF1 plays a critical role in determining the regenerative potential of stem cells. HSF1 does that by affecting exosome biogenesis and miRNA cargo sorting via regulation of YBX1 gene expression.

Safety and efficacy of transcoronary transfer of human neonatal stem cells to ischemic myocardium using a novel cell-delivery system (CIRCULATE catheter) in swine model of acute myocardial infarction.

Introduction: Stem cell-based therapies have shown promise in adults with ischemic cardiomyopathy and children with congenital heart diseases, especially those without available therapeutic options. Human neonatal mesenchymal stem cells (nMSCs) have greater regenerative potential than adult stem cells. Aim: To describe our experience with a novel catheter system for transcoronary delivery of cell-based therapies (CIRCULATE catheter) in the intra-coronary delivery of nMSCs in a swine acute myocardial infarct model. Material and methods: A newly developed catheter system (CIRCULATE catheter) with several unique features, including an expandable intra-coronary reservoir with spirally placed side holes of varying diameter, was used. nMSCs together with their secretome were used for the treatment. Pigs underwent myocardial infarction by inflating a 2.5 mm angioplasty balloon in the left anterior descending artery for 60 min. After reperfusion, stem cell therapy or placebo was administered via the novel catheter. TTE was performed at baseline, 1 h after the procedure, and before the euthanasia. Troponin blood concertation was evaluated at baseline, and after 48 h. The heart was harvested, sliced, and stained with triphenyl tetrazolium chloride (TTC). Infarct size to area-at-risk ratio was calculated. Troponin was assessed at baseline and after 48 h. Results: Thirty-nine pigs were operated with the mortality rate of 5.13% (exclusively malignant arrhythmia). Infarct size to area-at-risk ratio was significantly lower in the treatment group. Treated animals had higher ejection fraction than controls. Conclusions: Intra-coronary delivery of neonatal mesenchymal stem cells reduces the infarct size and restores myocardial function in a swine model. The novel catheter system (CIRCULATE catheter) tested in this study was safe and effective in transcoronary cell delivery of human neonatal mesenchymal stem cells.

Stem cell therapy for single ventricle congenital heart disease - current state and future directions.

Hypoplastic left heart syndrome (HLHS) is one of the most complex forms of congenital heart disease, characterized by an underdeveloped left ventricle, outflow tract and aorta. Current surgical and medical treatment for this disease remains palliative. As a result of the multi-step surgery, the right ventricle plays the role of the systemic ventricle, which inevitably leads to its failure. There is an urgent need to develop new treatments to ameliorate the right ventricle failure. Stem cell therapy may represent a new approach to single ventricle pathology. Great numbers of small and large animal studies have proven this therapy to be safe and effective in hypoplastic left heart syndrome. Several clinical trials have been designed to investigate the potential of mesenchymal stem cells in univentricular heart physiology. With increasing evidence, understanding of the mechanism of stem cells' action has shifted from the concept of differentiation into various heart cell types to paracrine activity playing the major role. The secretome of stem cells has been identified as their functional unit. In this review, we present different types of stem cells used in single ventricle diseases in children as well as their preclinical investigations. We also summarize clinical applications of stem cells in children with HLHS.

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4+ and CD8+ T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule - ARG1, mitigating anti-tumor immune responses.

Validation of the Polish version of P-QoL questionnaire.

OBJECTIVE: Pelvic organ prolapse (POP) is a common morbidity that affects many women and significantly decreases quality of life. The severity and the impact of the prolapse on the quality of life are important parameters in the management and follow-up of affected patients. The aim of this validation study was to validate the Polish version of the Prolapse Quality of Life questionnaire (P-QoL). MATERIAL AND METHODS: The P-QOL questionnaire was translated into Polish and administered to women recruited from two gynecological outpatient clinics (n = 231). Both symptomatic and asymptomatic women were included in the study and examined in supine position using the Pelvic Organ Prolapse Quantification System (POP-Q). The validity was assessed by comparing symptom scores and quality-of-life scores between symptomatic and asymptomatic women. RESULTS: A total number of 154 symptomatic and 77 asymptomatic women were included. There was a strong correlation between severity of the disease based on physical findings (POP-Q scale) and the P-QoL scores in main prolapse quality-of-life domains. The overall scores for each life domain were significantly different between symptomatic and asymptomatic women (p < 0.001). All the questions regarding symptoms showed significant differences (p < 0.001) between both groups. CONCLUSIONS: The Polish version of P-QoL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in Polish-speaking women suffering from urogenital prolapse.

Elective cesarean section on psychiatric indications - the phenomenon analysis, report of two cases and psychiatric clinical recommendations. / Elektywne ciecie cesarskie ze wskazan psychiatrycznych - analiza zjawiska, opis dwóch przypadków oraz rekomendacje kliniczne.

OBJECTIVES: In Poland, no guidelines concerning the mode of delivery in patients with psychiatric disorders have so far been developed. The most common psychiatric diagnosis discussed in the Polish literature in the context of the indications for the elective caesarean section is tokophobia. It was confirmed in recent studies that intense fear of childbirth, requiring medical interventions is an important predictor of postpartum depression. Other studies have shown that emergency delivery causes long lasting posttraumatic stress disorder symptoms. The aim of this paper is to discuss the different mental disorders, which may determine psychiatric indications for elective CS. METHODS: A literature review and analysis of two cases. Review of the literature was made via MEDLINE and based on such a keywords as: mental health, mode of delivery, caesarean section, psychiatric indications for CS. In the analysis, papers based on population studies and essential because of the potential clinical decisions concerning psychiatric indications for CS were taken into account first. RESULTS: Psychiatric indications for the preferred type of delivery are determined individually. They are mainly based on the ability of the psychiatric patient to cooperate with obstetric staff during vaginal delivery. The second area of psychiatric indications is a strong fear of labour that results in the need for psychiatric consultation in the last trimester of pregnancy or the perinatal period. CONCLUSIONS: Antenatal care of women with mental disorders requires close cooperation between the obstetricians and psychiatrists specialised in the mental disorders due to somatic state. Such cooperation should lead to preventing both obstetric and psychiatric complications during the pregnancy and labour in women experiencing symptoms of mental disorders.

["Mid-stimulation psychosis" in the course of in vitro fertilization procedure with the use of clomiphene citrate and bromocriptine - case study]. / Przypadek "psychozy okolostymulacyjnej" w przebiegu procedury zaplodnienia pozaustrojowego z zastosowaniem cytrynianu klomifenu oraz bromokryptyny.

AIM: A few cases of psychosis induced by clomiphene citrate have been described so far. However, data on the prevalence of psychotic symptoms among women treated for infertility are inconclusive. Still a little is known about possible psychiatric complications of medications used in assisted reproduction techniques (ART). We present a case of a patient who developed transient psychotic symptoms in the course of the in vitro fertilization procedures. To our kiiowledge, this is the first case of 'mid-stimulation psychosis', which has been observed during ART using clomiphene.citrate and bromocriptine. The aim of this study is to describe the determinants ofpharmacotherapy undertaken in ART,.which can result in the development of psychotic symptoms. METHODS: The Case presentation. CONCLUSIONS: The use of clomiphene citrate for ovulation induction in combination with bromocriptine used for chronic hyperprolactinemia is a likely mechanism that might have triggered psychotic symptoms in the case presented. However, combination therapy with clomiphen citrate and.bromocriptine may be the pharmacological model of hyper-dopaminergia followed by chaotic changes in serum estrogen levels and might lead to an increased sensitivity of dopamine receptors. The above therapeutic schema may increase susceptibility to the development of psychotic symptoms in treated women. This impact should be considered in the case of any psychotic complications in patients undergoing assisted reproduction techniques