Exploring stem cell fate from adipose tissue: novel approaches to modulate stem cell signatures

Stem cells (SCs), undifferentiated elements able to acquire specific phenotype upon stimulation, represent an important source for regenerative medicine, restoring function of compromised organs. The purpose of regenerative biology is to identify the cellular and molecular differences that distinguish normal tissue turnover from scar repair, in order to create an ideal microenvironment suitable for regeneration in damaged adult tissues. Stem cell differentiation is a complex process controlled by signaling pathways and molecular mechanisms, acting to maintain tissue homeostasis. A wide range of natural molecules and compounds, known as nutraceuticals or functional foods, are widely used for their therapeutic or preventive effects. These natural and synthetic molecules exert their action via epigenetic modulations of a specific molecular differentiation program and gene expression of lineage-specific markers. Within this context, unraveling the cellular mechanisms involved in the activation and differentiation of the adipose resident stem cells, could help in identifying innovative and preventive tools to counteract obesity and its related diseases. The aim of this project was to evaluate cell behavior in the presence of conditioned media, drugs or natural molecules, in the attempt to counteract the molecular mechanisms involved in inflammatory-associated adipogenesis. Understanding the molecular mechanisms involved in the decision of this fate could lead to the development of drugs capable of influencing stem cell behavior, for future in vivo clinical applications

Step-By-Step Community Detection in Volume-Regular Graphs

Spectral techniques have proved amongst the most effective approaches to graph clustering. However, in general they require explicit computation of the main eigenvectors of a suitable matrix (usually the Laplacian matrix of the graph). Recent work (e.g., Becchetti et al., SODA 2017) suggests that observing the temporal evolution of the power method applied to an initial random vector may, at least in some cases, provide enough information on the space spanned by the first two eigenvectors, so as to allow recovery of a hidden partition without explicit eigenvector computations. While the results of Becchetti et al. apply to perfectly balanced partitions and/or graphs that exhibit very strong forms of regularity, we extend their approach to graphs containing a hidden k partition and characterized by a milder form of volume-regularity. We show that the class of k-volume regular graphs is the largest class of undirected (possibly weighted) graphs whose transition matrix admits k "stepwise" eigenvectors (i.e., vectors that are constant over each set of the hidden partition). To obtain this result, we highlight a connection between volume regularity and lumpability of Markov chains. Moreover, we prove that if the stepwise eigenvectors are those associated to the first k eigenvalues and the gap between the k-th and the (k+1)-th eigenvalues is sufficiently large, the Averaging dynamics of Becchetti et al. recovers the underlying community structure of the graph in logarithmic time, with high probability

MiR200 and MiR302: Two big families influencing stem cell behavior

In this review, we described different factors that modulate pluripotency in stem cells, in particular we aimed at following the steps of two large families of miRNAs: the miR-200 family and the miR-302 family. We analyzed some factors tuning stem cells behavior as TGF-\uce\ub2, which plays a pivotal role in pluripotency inhibition together with specific miRNAs, reactive oxygen species (ROS), but also hypoxia, and physical stimuli, such as ad hoc conveyed electromagnetic fields. TGF-\uce\ub2 plays a crucial role in the suppression of pluripotency thus influencing the achievement of a specific phenotype. ROS concentration can modulate TGF-\uce\ub2 activation that in turns down regulates miR-200 and miR-302. These two miRNAs are usually requested to maintain pluripotency, while they are down-regulated during the acquirement of a specific cellular phenotype. Moreover, also physical stimuli, such as extremely-low frequency electromagnetic fields or high-frequency electromagnetic fields conveyed with a radioelectric asymmetric conveyer (REAC), and hypoxia can deeply influence stem cell behavior by inducing the appearance of specific phenotypes, as well as a direct reprogramming of somatic cells. Unraveling the molecular mechanisms underlying the complex interplay between externally applied stimuli and epigenetic events could disclose novel target molecules to commit stem cell fate

Biased Opinion Dynamics: When the Devil Is in the Details

We investigate opinion dynamics in multi-agent networks when a bias toward one of two possible opinions exists; for example, reflecting a status quo vs a superior alternative. Starting with all agents sharing an initial opinion representing the status quo, the system evolves in steps. In each step, one agent selected uniformly at random adopts the superior opinion with some probability $\alpha$, and with probability $1 - \alpha$ it follows an underlying update rule to revise its opinion on the basis of those held by its neighbors. We analyze convergence of the resulting process under two well-known update rules, namely majority and voter. The framework we propose exhibits a rich structure, with a non-obvious interplay between topology and underlying update rule. For example, for the voter rule we show that the speed of convergence bears no significant dependence on the underlying topology, whereas the picture changes completely under the majority rule, where network density negatively affects convergence. We believe that the model we propose is at the same time simple, rich, and modular, affording mathematical characterization of the interplay between bias, underlying opinion dynamics, and social structure in a unified setting.Comment: The paper has appeared in the Proceedings of the Twenty-Ninth International Joint Conference on Artificial Intelligence. The SOLE copyright holder is IJCAI (International Joint Conferences on Artificial Intelligence), all rights reserved. Link to the proceedings: https://www.ijcai.org/Proceedings/2020/

Management of Obesity and Obesity-Related Disorders: From Stem Cells and Epigenetics to Its Treatment

: Obesity is a complex worldwide disease, characterized by an abnormal or excessive fat accumulation. The onset of this pathology is generally linked to a complex network of interactions among genetic and environmental factors, aging, lifestyle, and diets. During adipogenesis, several regulatory mechanisms and transcription factors are involved. As fat cells grow, adipose tissue becomes increasingly large and dysfunctional, losing its endocrine function, secreting pro-inflammatory cytokines, and recruiting infiltrating macrophages. This long-term low-grade systemic inflammation results in insulin resistance in peripheral tissues. In this review we describe the main mechanisms involved in adipogenesis, from a physiological condition to obesity. Current therapeutic strategies for the management of obesity and the related metabolic syndrome are also reported

Mechanical Stimulation of Fibroblasts by Extracorporeal Shock Waves: Modulation of Cell Activation and Proliferation Through a Transient Proinflammatory Milieu

Extracorporeal shock waves (ESWTs) are "mechanical" waves, widely used in regenerative medicine, including soft tissue wound repair. Although already being used in the clinical practice, the mechanism of action underlying their biological activities is still not fully understood. In the present paper we tried to elucidate whether a proinflammatory effect may contribute to the regenerative potential of shock waves treatment. For this purpose, we exposed human foreskin fibroblasts (HFF1 cells) to an ESWT treatment (100 pulses using energy flux densities of 0.19 mJ/mm2 at 3 Hz), followed by cell analyses after 5 min, up to 48 h. We then evaluated cell proliferation, reactive oxygen species generation, ATP release, and cytokine production. Cells cultured in the presence of lipopolysaccharide (LPS), to induce inflammation, were used as a positive control, indicating that LPS-mediated induction of a proinflammatory pattern in HFF1 increased their proliferation. Here, we provide evidence that ESWTs affected fibroblast proliferation through the overexpression of selected cytokines involved in the establishment of a proinflammatory program, superimposable to what was observed in LPS-treated cells. The possibility that inflammatory circuits can be modulated by ESWT mechanotransduction may disclose novel hypothesis on their biological underpinning and expand the fields of their biomedical application

Myrtus polyphenols, from antioxidants to anti-inflammatory molecules: Exploring a network involving cytochromes P450 and Vitamin D

Inflammatory response represents one of the main mechanisms of healing and tissue function restoration. On the other hand, chronic inflammation leads to excessive secretion of pro-inflammatory cytokines involved in the onset of several diseases. Oxidative stress condition may contribute in worsening inflammatory state fall, increasing reactive oxygen species (ROS) production and cytokines release. Polyphenols can counteract inflammation and oxidative stress, modulating the release of toxic molecules and interacting with physiological defenses, such as cytochromes p450 enzymes. In this paper, we aimed at evaluating the anti-inflammatory properties of different concentrations of Myrtus communis L. pulp and seeds extracts, derived from liquor industrial production, on human fibroblasts. We determined ROS production after oxidative stress induction by H 2 O 2 treatment, and the gene expression of different proinflammatory cytokines. We also analyzed the expression of CYP3A4 and CYP27B1 genes, in order to evaluate the capability of Myrtus polyphenols to influence the metabolic regulation of other molecules, including drugs, ROS, and vitamin D. Our results showed that Myrtus extracts exert a synergic effect with vitamin D in reducing inflammation and ROS production, protecting cells from oxidative stress damages. Moreover, the extracts modulate CYPs expression, preventing chronic inflammation and suggesting their use in development of new therapeutic formulations

Step-by-step community detection in volume-regular graphs

International audienceSpectral techniques have proved amongst the most effective approaches to graph clustering. However, in general they require explicit computation of the main eigenvectors of a suitable matrix (usuallythe Laplacian matrix of the graph).Recent work (e.g., Becchetti et al., SODA 2017) suggests that observing the temporal evolutionof the power method applied to an initial random vector may, at least in some cases, provide enoughinformation on the space spanned by the first two eigenvectors, so as to allow recovery of a hiddenpartition without explicit eigenvector computations. While the results of Becchetti et al. applyto perfectly balanced partitions and/or graphs that exhibit very strong forms of regularity, weextend their approach to graphs containing a hiddenkpartition and characterized by a milderform of volume-regularity. We show that the class ofk-volume regulargraphs is the largest class ofundirected (possibly weighted) graphs whose transition matrix admitsk“stepwise” eigenvectors (i.e.,vectors that are constant over each set of the hidden partition). To obtain this result, we highlight aconnection between volume regularity and lumpability of Markov chains. Moreover, we prove that ifthe stepwise eigenvectors are those associated to the firstkeigenvalues and the gap between thek-th and the (k+1)-th eigenvalues is sufficiently large, theAveragingdynamics of Becchetti et al.recovers the underlying community structure of the graph in logarithmic time, with high probabi

Melatonin and Vitamin D Interfere with the Adipogenic Fate of Adipose-Derived Stem Cells

Adipose-derived stem cells (ADSCs) represent one of the cellular populations resident in adipose tissue. They can be recruited under certain stimuli and committed to become preadipocytes, and then mature adipocytes. Controlling stem cell differentiation towards the adipogenic phenotype could have a great impact on future drug development aimed at counteracting fat depots. Stem cell commitment can be influenced by different molecules, such as melatonin, which we have previously shown to be an osteogenic inducer. Here, we aimed at evaluating the effects elicited by melatonin, even in the presence of vitamin D, on ADSC adipogenesis assessed in a specific medium. The transcription of specific adipogenesis orchestrating genes, such as aP2, peroxisome proliferator-activated receptor \u3b3 (PPAR-\u3b3), and that of adipocyte-specific genes, including lipoprotein lipase (LPL) and acyl-CoA thioesterase 2 (ACOT2), was significantly inhibited in cells that had been treated in the presence of melatonin and vitamin D, alone or in combination. Protein content and lipid accumulation confirmed a reduction in adipogenesis in ADSCs that had been grown in adipogenic conditions, but in the presence of melatonin and/or vitamin D. Our findings indicate the role of melatonin and vitamin D in deciding stem cell fate, and disclose novel therapeutic approaches against fat depots

Identifying a Role of Red and White Wine Extracts in Counteracting Skin Aging: Effects of Antioxidants on Fibroblast Behavior

Dermal fibroblasts are the main actor in many proteins' secretion, including collagen, preserving skin function. Free radicals are involved in skin aging and damages involving different cellular components. The imbalance between reactive oxygen species (ROS) amount and natural antioxidant enzymes negatively affects skin homeostasis. Natural compounds have recently emerged as a potential anti-aging tool in tissue regeneration. In the present paper we evaluated the antioxidant activity of white and red wines, considering their probable use, as raw materials, for the formulation of cosmetic products with anti-aging properties. We studied a method that would allow the removal of the alcoholic fraction of wines and determined their composition by LC-MS analysis. We then tested the possible cytotoxic effects of red and white wines on fibroblasts by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, and their antioxidant activity by the catalase activity test in stressing conditions. Finally, we evaluated their anti-aging potential through the beta-galactosidase colorimetric assay. Our results showed that wine extracts exhibit a remarkable antioxidant and anti-aging activity, especially on cells exposed to a marked stressful event. These properties could suggest their possible application as cosmetical products for skin regeneration