Why are MSCs therapeutic? New data: new insight.
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ABSTRACT:
SUBMITTER: Caplan AI
PROVIDER: S-EPMC8793150 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Project description:Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.
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Project description:Even small variations of serum sodium concentration may be associated with mortality. Our objective was to confirm the impact of borderline dysnatremia for patients admitted to hospital on in-hospital mortality using real life care data from our electronic health record (EHR) and a phenome-wide association analysis (PheWAS).Retrospective observational study based on patient data admitted to Hôpital Européen George Pompidou, between 01/01/2008 and 31/06/2014; including 45,834 patients with serum sodium determinations on admission. We analyzed the association between dysnatremia and in-hospital mortality, using a multivariate logistic regression model to adjust for classical potential confounders. We performed a PheWAS to identify new potential confounders.Hyponatremia and hypernatremia were recorded for 12.0% and 1.0% of hospital stays, respectively. Adjusted odds ratios (ORa) for severe, moderate and borderline hyponatremia were 3.44 (95% CI, 2.41-4.86), 2.48 (95% CI, 1.96-3.13) and 1.98 (95% CI, 1.73-2.28), respectively. ORa for severe, moderate and borderline hypernatremia were 4.07 (95% CI, 2.92-5.62), 4.42 (95% CI, 2.04-9.20) and 3.72 (95% CI, 1.53-8.45), respectively. Borderline hyponatremia (ORa?=?1.57 95% CI, 1.35-1.81) and borderline hypernatremia (ORa?=?3.47 95% CI, 2.43-4.90) were still associated with in-hospital mortality after adjustment for classical and new confounding factors identified through the PheWAS analysis.Borderline dysnatremia on admission are independently associated with a higher risk of in-hospital mortality. By using medical data automatically collected in EHR and a new data mining approach, we identified new potential confounding factors that were highly associated with both mortality and dysnatremia.
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Project description:The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt's lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers.
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Project description:The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer's disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.
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Project description:BackgroundThe data missing from patient profiles in intensive care units (ICUs) are substantial and unavoidable. However, this incompleteness is not always random or because of imperfections in the data collection process.ObjectiveThis study aimed to investigate the potential hidden information in data missing from electronic health records (EHRs) in an ICU and examine whether the presence or missingness of a variable itself can convey information about the patient health status.MethodsDaily retrieval of laboratory test (LT) measurements from the Medical Information Mart for Intensive Care III database was set as our reference for defining complete patient profiles. Missingness indicators were introduced as a way of representing presence or absence of the LTs in a patient profile. Thereafter, various feature selection methods (filter and embedded feature selection methods) were used to examine the predictive power of missingness indicators. Finally, a set of well-known prediction models (logistic regression [LR], decision tree, and random forest) were used to evaluate whether the absence status itself of a variable recording can provide predictive power. We also examined the utility of missingness indicators in improving predictive performance when used with observed laboratory measurements as model input. The outcome of interest was in-hospital mortality and mortality at 30 days after ICU discharge.ResultsRegardless of mortality type or ICU day, more than 40% of the predictors selected by feature selection methods were missingness indicators. Notably, employing missingness indicators as the only predictors achieved reasonable mortality prediction on all days and for all mortality types (for instance, in 30-day mortality prediction with LR, we achieved area under the curve of the receiver operating characteristic [AUROC] of 0.6836±0.012). Including indicators with observed measurements in the prediction models also improved the AUROC; the maximum improvement was 0.0426. Indicators also improved the AUROC for Simplified Acute Physiology Score II model-a well-known ICU severity of illness score-confirming the additive information of the indicators (AUROC of 0.8045±0.0109 for 30-day mortality prediction for LR).ConclusionsOur study demonstrated that the presence or absence of LT measurements is informative and can be considered a potential predictor of in-hospital and 30-day mortality. The comparative analysis of prediction models also showed statistically significant prediction improvement when indicators were included. Moreover, missing data might reflect the opinions of examining clinicians. Therefore, the absence of measurements can be informative in ICUs and has predictive power beyond the measured data themselves. This initial case study shows promise for more in-depth analysis of missing data and its informativeness in ICUs. Future studies are needed to generalize these results.
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Project description:The ERp57/PDIA3 protein is a pleiotropic member of the PDIs family and, although predominantly located in the endoplasmic reticulum (ER), has indeed been found in other cellular compartments, such as the nucleus or the cell membrane. ERp57/PDIA3 is an important research target considering it can be found in various subcellular locations. This protein is involved in many different physiological and pathological processes, and our review describes new data on its functions and summarizes some ligands identified as PDIA3-specific inhibitors.
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Project description:Bone marrow mesenchymal stem cell (MSC) therapy acts through multiple differentiations in damaged tissue or via secretion of paracrine factors, as demonstrated in various inflammatory and ischaemic diseases. However, long-term ex vivo culture to obtain a sufficient number of cells in MSC transplantation leads to cellular senescence, deficiency of the paracrine potential, and loss of survival rate post-transplantation. In this study, we evaluated whether supplementation of MSCs with substance P (SP) can improve their therapeutic potential. SP treatment elevated the secretion of paracrine/angiogenic factors, including VEGF, SDF-1a and PDGF-BB, from late passage MSCs in vitro. MSCs supplemented with SP accelerated epidermal/dermal regeneration and neovascularization and suppressed inflammation in vivo, compared to MSCs transplanted alone. Importantly, supplementation with SP enabled the incorporation of transplanted human MSCs into the host vasculature as pericytes via PDGF signalling, leading to the direct engagement of transplanted cells in compact vasculature formation. Our results showed that SP is capable of restoring the cellular potential of senescent stem cells, possibly by modulating the generation of paracrine factors from MSCs, which might accelerate MSC-mediated tissue repair. Thus, SP is anticipated to be a potential beneficial agent in MSC therapy for inflammatory or ischaemic diseases and cutaneous wounds.
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