Environmental microplastics (EMPs) exposure alter the differentiation potential of mesenchymal stromal cells.

Humans are exposed to environmental microplastic (MPs) that can be frequent in surrounding environment. The mesenchymal stromal cells are a heterogeneous population, which contain fibroblasts and stromal cells, progenitor cells and stem cells. They are part of the stromal component of most tissue and organs in our organisms. Any injury to their functions may impair tissue renewal and homeostasis. We evaluated the effects of different size MPs that could be present in water bottles on human bone marrow mesenchymal stromal cells (BMMSCs) and adipose mesenchymal stromal cells (AMSCs). MPs of polyethylene terephthalate (MPs-PET) (<1 µm and <2.6 µm) were tested in this study. PET treatments induced a reduction in proliferating cells (around 30%) associated either with the onset of senescence or increase in apoptosis. The AMSCs and BMMSCs exposed to PET showed an alteration of differentiation potential. AMSCs remained in an early stage of adipocyte differentiation as shown by high levels of mRNA for Peroxisome Proliferator Activated Receptor Gamma (PPARG) (7.51 vs 1.00) and reduction in Lipoprotein Lipase (LPL) mRNA levels (0.5 vs 1.0). A loss of differentiation capacity was also observed for the osteocyte phenotype in BMMSCs. In particular, we observed a reduction in Bone Gamma-Carboxy glutamate Protein (BGLAP) (0.4 for PET1 and 0.6 for PET2.6 vs 0.1 CTRL) and reduction in Osteopontin (SPP1) (0.3 for PET 1 and 0.64 for PET 2.6 vs 0.1 CTRL). This pioneering mesenchymal cell response study demonstrated that environmental microplastic could be bioavailable for cell uptake and may further lead to irreversible diseases.

Cellular Senescence in Physiological and Pathological Processes.

This Special Issue aims to address the impact of cellular senescence on human biology, looking at both physiological and pathological processes [...].

Biomolecular Evaluation of Piceatannol's Effects in Counteracting the Senescence of Mesenchymal Stromal Cells: A New Candidate for Senotherapeutics?

Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body's homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol's effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol's various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes.

Micro-RNAs: Crossroads between the Exposure to Environmental Particulate Pollution and the Obstructive Pulmonary Disease.

Environmental pollution has reached a global echo and represents a serious problem for human health. Air pollution encompasses a set of hazardous substances, such as particulate matter and heavy metals (e.g., cadmium, lead, and arsenic), and has a strong impact on the environment by affecting groundwater, soil, and air. An adaptive response to environmental cues is essential for human survival, which is associated with the induction of adaptive phenotypes. The epigenetic mechanisms regulating the expression patterns of several genes are promising candidates to provide mechanistic and prognostic insights into this. Micro-RNAs (miRNAs) fulfil these features given their ability to respond to environmental factors and their critical role in determining phenotypes. These molecules are present in extracellular fluids, and their expression patterns are organ-, tissue-, or cell-specific. Moreover, the experimental settings for their quantitative and qualitative analysis are robust, standardized, and inexpensive. In this review, we provide an update on the role of miRNAs as suitable tools for understanding the mechanisms behind the physiopathological response to toxicants and the prognostic value of their expression pattern associable with specific exposures. We look at the mechanistic evidence associable to the role of miRNAs in the processes leading to environmental-induced pulmonary disease (i.e., chronic obstructive pulmonary disease).

Metabolic syndrome, Mediterranean diet, and polyphenols: Evidence and perspectives.

Metabolic syndrome (MetS) is defined as the co-occurrence of metabolic risk factors that includes insulin resistance, hyperinsulinemia, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The clinical significance of MetS consists of identifying a subgroup of patients sharing a common physiopathological state predisposing to chronic diseases. Clinical and scientific studies pinpoint lifestyle modification as an effective strategy aiming to reduce several features accountable for the risk of MetS onset. Among the healthy dietary patterns, the Mediterranean diet (MedDiet) emerges in terms of beneficial properties associated with longevity. Current evidence highlights the protective effect exerted by MedDiet on the different components of MetS. Interestingly, the effect exerted by polyphenols contained within the representative MedDiet components (i.e., olive oil, red wine, and nuts) seems to be accountable for the beneficial properties associated to this dietary pattern. In this review, we aim to summarize the principal evidence regarding the effectiveness of MedDiet-polyphenols in preventing or delaying the physiopathological components accountable for MetS onset. These findings may provide useful insights concerning the health properties of MedDiet-polyphenols as well as the novel targets destined to a tailored approach to MetS.

Concise Review: The Effect of Low-Dose Ionizing Radiation on Stem Cell Biology: A Contribution to Radiation Risk.

Exposure to high levels of ionizing radiation (IR) (>0.5 Gy) negatively affects health, but less is known about the effects of low-dose ionizing radiation (LDIR). Recent evidence suggests that it may have profound effects on cellular functions. People are commonly exposed to LDIR over natural background levels from numerous sources, including LDIR from medical diagnosis and therapy, air travel, illegal IR waste dumpsites, and occupational exposures in the nuclear and medical sectors. Stem cells reside for long periods of time in our bodies, and this increases the possibility that they may accumulate genotoxic damage derived from extrinsic LDIR or intrinsic sources (such as DNA replication). In this review, we provide an overview of LDIR effects on the biology of stem cell compartments. The principal findings and issues reported in the scientific literature are discussed in order to present the current understanding of the LDIR exposure risk and assess whether it may impact human health. We first consider the general biological consequences of LDIR exposure. Following this, we discuss the effects of LDIR on stem cells as discovered through in vitro and in vivo studies. Stem Cells 2018;36:1146-1153.

Senescence Phenomena and Metabolic Alteration in Mesenchymal Stromal Cells from a Mouse Model of Rett Syndrome.

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.

Adult-onset brain tumors and neurodegeneration: Are polyphenols protective?

Aging is a primary risk factor for both neurodegenerative disorders (NDs) and tumors such as adult-onset brain tumors. Since NDs and tumors are severe, disabling, progressive and often incurable conditions, they represent a pressing problem in terms of human suffering and economic costs to the healthcare systems. The current challenge for physicians and researchers is to develop new therapeutic strategies in both areas to improve the patients' quality of life. In addition to genetics and environmental stressors, the increase in cellular oxidative stress as one of the potential common etiologies has been reported for both disorders. Recently, the scientific community has focused on the beneficial effects of dietary antioxidant classes, known as nutraceuticals, such as carotenoids, vitamins, and polyphenols. Among these compounds, polyphenols are considered to be one of the most bioactive agents in neurodegeneration and tumor prevention. Despite the beneficial activity of polyphenols, their poor bioavailability and inefficient delivery systems are the main factors limiting their use in medicine and functional food. The development of polymeric nanoparticle-based delivery systems able to encapsulate and preserve polyphenolic compounds may represent a promising tool to enhance their stability, solubility, and cell membrane permeation. In the present review we provide an overview of the main polyphenolic compounds used for ND and brain tumor prevention and treatment that explores their mechanisms of action, recent clinical findings and principal factors limiting their application in medicine.

Stem Cells and DNA Repair Capacity: Muse Stem Cells Are Among the Best Performers.

Stem cells persist for long periods in the body and experience many intrinsic and extrinsic stresses. For this reason, they present a powerful and effective DNA repair system in order to properly fix DNA damage and avoid the onset of a degenerative process, such as neoplastic transformation or aging. In this chapter, we compare the DNA repair ability of pluripotent stem cells (ESCs, iPSCs, and Muse cells) and other adult stem cells. We also describe personal investigations showing a robust and effective capacity of Muse cells in sensing and repairing DNA following chemical and physical stress. Muse cells can repair DNA through base and nucleotide excision repair mechanisms, BER and NER, respectively. Furthermore, they present a pronounced capacity in repairing double-strand breaks by the nonhomologous end joining (NHEJ) process. The studies addressing the role of DNA damage repair in the biology of stem cells are of paramount importance for comprehension of their functions and, also, for setting up effective and safe stem cell-based therapy.

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes.

Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1 hr after oxidative stress induction and a return to basal level at 48 hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity.