The Role of Oxygen Tension and Insulin-Like Growth Factor Signaling in the Placental Mesenchymal Stem Cell Fate

The human placenta of different gestational ages is a readily available source for isolation of adult mesenchymal stem cell (MSC) for potential use in regenerative therapies. The chorionic villous region, the largest component of a placenta that interfaces with the maternal circulation, is a rich source of placental MSCs (PMSCs). To remain multipotent, PMSCs are best maintained in culture conditions that mimic the in vivo microenvironment. Insulin like growth factors (IGFs, IGF-I and -II) and oxygen tension are two of the most important microenvironmental factors in the placenta. They are of low concentration or tension respectively, at early gestation, and increase as pregnancy progresses. In this thesis, we investigated the role and cellular mechanisms by which IGFs and low oxygen tension determine PMSC fate. The main hypothesis is that the interaction between IGFs and oxygen tension determines PMSC fate towards self-renewal or differentiation. We used cell proliferation assay, immunoblotting, real-time PCR, and cell monolayer staining to evaluate the role of IGF and oxygen tension on PMSC multipotency and differentiation. We found that low oxygen tension was a major determinant of PMSCs proliferation and multipotency, and to delay differentiation. Also, PMSC response to IGF stimulation and low oxygen tension was gestational age dependent — preterm PMSCs being more multipotent and proliferative than term PMSCs. IGF-I and IGF-II promoted PMSC proliferation and multipotency via IGF-IR or IR, depending on oxygen tension. IGFs enhanced PMSC differentiation towards the osteogenic lineage which was transduced by ERK1/2 and AKT signaling cascades. We conclude that IGFs and oxygen tension act synergistically or antagonistically, mimicking in vivo microenvironmental conditions, to determine PMSC fate towards multipotency or differentiation. The appropriate combination of IGFs and oxygen tension can be used to maintain stem cells in multipotency, or to be induced towards a specific progenitor cell lineage for successful use in tissue regeneration therapies

Regulation of Osteogenic Differentiation of Placental-Derived Mesenchymal Stem Cells by Insulin-Like Growth Factors and Low Oxygen Tension

Placental mesenchymal stem cells (PMSCs) are multipotent cells that can differentiate in vitro to multiple lineages, including bone. Insulin-like growth factors (IGFs, IGF-1 and IGF-2) participate in maintaining growth, survival, and differentiation of many stem cells, including osteoprogenitors. Low oxygen tension (PO2) can maintain stem cell multipotency and impede osteogenic differentiation. In this study, we investigated whether PMSC osteogenic differentiation is influenced by low PO2 and by IGFs. Our results indicated that low PO2 decreased osteogenic markers RUNX2 and OPN; however, re-exposure to higher oxygen tension (room air) restored differentiation. IGFs, especially IGF-1, triggered an earlier expression of RUNX2 and enhanced OPN and mineralization. RUNX2 was phosphorylated in room air and augmented by IGFs. IGF-1 receptor (IGF-1R) was increased in low PO2 and reduced by IGFs, while insulin receptor (IR) was increased in differentiating PMSCs and enhanced by IGF-1. Low PO2 and IGFs maintained higher IR-A which was switched to IR-B in room air. PI3K/AKT was required for osteogenic differentiation, while MEK/ERK was required to repress an RUNX2 and OPN increase in low PO2. Therefore, IGFs, specifically IGF-1, trigger the earlier onset of osteogenic differentiation in room air, whereas, reversibly, low PO2 impedes complete differentiation by maintaining higher multipotency and lower differentiation markers

The Roles of Insulin-Like Growth Factors in Mesenchymal Stem Cell Niche

Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers

Simplified structural analysis of framed ordinary non-tempered glass panels during fire exposure

Ordinary non-tempered glass is one of the most widely used materials in the construction industry. Knowing its fire resistance is essential to ensure the safety of emergency personnel as its failure increases the oxygen supply and causes a rapid spread of the fire (flashover phenomenon). Existing approaches for evaluating the structural fire safety of glass façades require expensive experimental tests and/or extensive knowledge of Finite Element modeling. This paper provides a simplified, rational, and reliable approach to assess the structural capacity of ordinary glass panels during fire exposure. A simplified method is developed to predict the temperature difference between the edge and the center of the glass panel. Afterward, a method, based on strain-equilibrium, is developed to predict the corresponding maximum thermal stress. The developed methods are validated by comparisons with experimental work by others

Moral Hazard Reduction in Entrepreneurial Financing An application to Profit and Loss Sharing Contracts

In profit and loss sharing contracts, profits are shared according to a specific ratio while losses are shared according to each partner contribution ration in the project’s capital. We aim to reduce entrepreneurial effort shirking in a profit and loss sharing contract involving a VC and an entrepreneur. We use a game theoretic approach and try to find the profit-sharing ratio that would reduce the moral hazard risk of effort shirking. The game theoretic approach allows for the development of a profit-sharing ratio span of negotiation that fulfil both the incentive and participative constraints of the PLS participant

Vital signs prediction and early warning score calculation based on continuous monitoring of hospitalised patients using wearable technology

In this prospective, interventional, international study, we investigate continuous monitoring of hospitalised patients’ vital signs using wearable technology as a basis for real-time early warning scores (EWS) estimation and vital signs time-series prediction. The collected continuous monitored vital signs are heart rate, blood pressure, respiration rate, and oxygen saturation of a heterogeneous patient population hospitalised in cardiology, postsurgical, and dialysis wards. Two aspects are elaborated in this study. The first is the high-rate (every minute) estimation of the statistical values (e.g., minimum and mean) of the vital signs components of the EWS for one-minute segments in contrast with the conventional routine of 2 to 3 times per day. The second aspect explores the use of a hybrid machine learning algorithm of kNN-LS-SVM for predicting future values of monitored vital signs. It is demonstrated that a real-time implementation of EWS in clinical practice is possible. Furthermore, we showed a promising prediction performance of vital signs compared to the most recent state of the art of a boosted approach of LSTM. The reported mean absolute percentage errors of predicting one-hour averaged heart rate are 4.1, 4.5, and 5% for the upcoming one, two, and three hours respectively for cardiology patients. The obtained results in this study show the potential of using wearable technology to continuously monitor the vital signs of hospitalised patients as the real-time estimation of EWS in addition to a reliable prediction of the future values of these vital signs is presented. Ultimately, both approaches of high-rate EWS computation and vital signs time-series prediction is promising to provide efficient cost-utility, ease of mobility and portability, streaming analytics, and early warning for vital signs deterioration

Effect of pulmonary rehabilitation programme including either O2 inhalation or noninvasive ventilation in patients with chronic obstructive pulmonary disease

Background: Pulmonary rehabilitation (PR) is crucial in managing chronic obstructive pulmonary disease (COPD) and enhancing functional capacity and health status. Oxygen therapy and noninvasive ventilation (NIV) may be needed to be incorporated into rehabilitation to augment the effectiveness of physical training. Objectives: To compare and assess the impact of the PR programme alone and with augmentation with O2 or NIV on COPD patients. Methods: Seventy-five COPD patients were equally divided into three groups: group 1 patients performed 8 week-PR programme only. Group 2 performed the PR programme while receiving O2. Group 3 completed the PR programme plus NIV. Modified Borg scale, VO2 max, modified Medical Research Council Dyspnea Scale, 6-minute walk test, COPD assessment test score, spirometric measures and arterial blood gases were assessed before and after the programme. Results: The outcome measurements showed meaningful improvement compared with the baseline in the three studied groups. However, VO2 max in group 3 showed higher significant improvement than both groups 1 and 2. Regarding 6-minute walk test, groups 2 and 3 had a higher significant improvement than group 1. COPD assessment test score in group 3 showed higher significant improvement than groups 1 and 2. Arterial blood gases in groups 2 and 3 showed significant increase in partial pressure of arterial oxygen and arterial oxygen saturation, but group 3 only had a significant decrease in PaCO2. Conclusion: O2 supplementation and NIV help severe to very severe COPD patients to perform higher exercise intensity, so they augment the benefits of PR

Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages

IntroductionLipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined.Methods and resultsTo explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1β and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1β release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation.DiscussionOur data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory