Mitochondria are highly dynamic organelles that in response to the cell's bio-energetic state continuously undergo structural remodeling fission and fusion processes. This mitochondrial dynamic activity has been implicated in cell cycle, autophagy, and age-related diseases. Adult tissue-derived mesenchymal stromal/stem cells present a therapeutic potential. However, to obtain an adequate mesenchymal stromal/stem cell number for clinical use, extensive in vitro expansion is required. Unfortunately, these cells undergo replicative senescence rapidly by mechanisms that are not well understood. Senescence has been associated with metabolic changes in the oxidative state of the cell, a process that has been also linked to mitochondrial fission and fusion events, suggesting an association between mitochondrial dynamics and senescence. In the present work, we studied the mitochondrial structural remodeling process of mesenchymal stromal/stem cells isolated from adipose tissue in vitro to determine if mitochondrial phenotypic changes were associated with mesenchymal stromal/stem cell senescence. For this purpose, mitochondrial dynamics and oxidative state of stromal/stem cell were compared between young and old cells. With increased cell passage, we observed a significant change in cell morphology that was associated with an increase in β-galactosidase activity. In addition, old cells (population doubling seven) also showed increased mitochondrial mass, augmented superoxide production, and decreased mitochondrial membrane potential. These changes in morphology were related to slightly levels increases in mitochondrial fusion proteins, Mitofusion 1 (MFN1), and Dynamin-related GTPase (OPA1). Collectively, our results showed that adipose tissue-derived MSCs at population doubling seven developed a senescent phenotype that was characterized by metabolic cell changes that can lead to mitochondrial fusion.

Breast cancer is the most common type of cancer and the leading cause of death among women. Recent evidence suggests that mesenchymal stromal/stem cells and cancer‐associated fibroblasts (CAFs) have an essential role in cancer progression, invasion and therapy resistance. Therefore, they are considered as highly promising future therapeutic targets against breast cancer. The intrinsic tumour tropism and immunomodulatory capacities of mesenchymal stromal/stem cells are of special relevance for developing mesenchymal stromal/stem cells‐based anti‐tumour therapies that suppress primary tumour growth and metastasis. In addition, the utilization of therapies that target the stromal components of the tumour microenvironment in combination with standard drugs is an innovative tool that could improve patients’ response to therapies and their survival. In this review, we discuss the currently available information regarding the possible use of mesenchymal stromal/stem cells‐derived anti‐tumour therapies, as well as the utilization of therapies that target CAFs in breast cancer microenvironment. Finally, these data can serve as a guide map for future research in this field, ultimately aiding the effective transition of these results into the clinic.

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The deregulation of the inflammatory cytokine interleukin (IL)-6 has been associated to a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The aim of this work was to analyze the variation of IL-6 levels in blood and damaged tissues during the course of the disease. We studied IL-6 protein expression in spinal cord, extensor digital longus (EDL) muscle and soleus (SOL) muscle of the SOD1G93A animal model at four stages of the disease by western blot. Concurrently, we analyzed IL-6 gene and protein expression in blood of ALS patients, healthy subjects and patients with other neuropathies through RTqPCR and ELISA. The results revealed different expression patterns depending on both the tissue analyzed and the stage of the disease, showing increasing IL-6 levels in EDL muscle over time. Moreover, lower IL-6 levels in blood were found in ALS patients. The decreased levels of IL-6 in blood from ALS patients could suggest that IL-6 might not be the main pro-inflammatory biomarker in the last stages in whole blood. In contrast, IL-6 may play a main role in fast glycolytic muscle fibers associated with muscle atrophy, suggesting that modulation of IL-6 in this tissue could be a potential target for anti-inflammatory therapies in ALS.

Viscoelastic fluids are a type of non-Newtonian fluids which are formed by complex internal structures and high-molecular-weight, whose typical examples are the polymer solutions and molten polymers. Also, the viscoleastic fluid flow presents a combination of two fluid properties: viscosity and elasticity. The main characteristic regarding the behavior of these flows is the strong dependence of the stresses on the flow history. Due to this complexity, computing the viscoelastic fluid flow involves a wide range of difficulties, in particular when elasticity becomes dominant, i.e., when the dimensionless Weissenberg number is high. These difficulties are considered one of the biggest challenges in computational rheology; this is known as the High Weissenberg Number Problem (HWNP). This study presents different strategies to deal with the numerical shortcomings that appear when the viscoelastic fluid is particularly elastic. These strategies are carried out in the Finite Element (FE) framework and by using the Variational Multiscale (VMS) formulation as stabilization approach. A term-by-term is also design. The cornerstone of this work is the application of a reformulation of the equations associated to the standard formulation, namely, the logarithmic reformulation, which permits simulating more elastic flows due to the fact that it eliminates the exponential stress profiles in the vicinity of stress singularities. Another topic addressed in this work is the study of the effect of temperature in viscoelastic fluid flow, where a two-way strategy is considered: the viscoelastic properties have now a dependence with the temperature, and the energy equation takes into account has to consider the viscous dissipation. That study is particularly interesting due to the fact that non-isothermal flow in many industrial applications. On the other hand, the incorporation of time-dependent subscales for solving the viscoelastic fluid flow problem is crucial to address two issues: the first one related with the instability produced when solving anisotropic space-time discretizations, and the second, the already mentioned exponential growth typical in viscoelastic flows with high Weissenberg number. In this work, time-dependent subgrid-scales are presented for both formulations: standard and logarithmic. Finally, as the logarithmic formulation is particularly expensive, above all when the scheme considered is monolithic, a fractional step for this formulation is designed, in which the system of equations is defined in a fully decoupled manner. This algorithm is especially useful when purely elastic instabilities need to be captured. These instabilities lead in some cases to elastic turbulence: a physical phenomenon in which the fluid flow becomes chaotic even for low Reynolds numbers. Los fluidos viscoelásticos son un tipo específico de fluidos no Newtonianos formados por una estructura interna muy compleja con alto peso molecular. Los ejemplos típicos de este tipo de fluidos son las soluciones y líquidos poliméricos. Además, los fluidos viscoelásticos presentan la combinación de dos propiedades específicas de los fluidos: viscosidad y elasticidad. Sin embargo, la principal característica relacionada con el comportamiento para estos flujos es la dependencia de la tensiones a la historia del fluido. Debido a su estructura y la complejidad de su comportamiento, resolver el problema de flujo viscoelástico se convierte en algo bastande difícil de abordar, en particular cuando el flujo es elástico, o en otras palabras, cuando el número adimensional Weissenberg es alto. Afrontar estas dificultades se considerada uno de los mayores retos de la reología computacional, y es conocido como el Problema de Alto Número de Weissenberg (HWNP). Este estudio presenta diferentes estrategias con el fin de evitar las dificultades numéricas que aparecen en estos casos, en que la componente elástica del fluido es muy dominante. Estas estrategias se abordan desde el marco de los Elementos Finitos cuyo método de estabilización será el de Subscalas Variacionales (VMS). Además, se diseña la estabilización término a término basada en estos métodos, que se aplicará a las formulaciones desarrolladas. Sin embargo, la piedra angular de este trabajo es la aplicación de una reformulación de las ecuaciones que describen el flujo viscoelástico, llamada formulación logaritmica, y que permite la simulación de casos más elásticos debido a que, básicamente, elimina el crecimiento exponencial de las tensiones cerca de singularidades. Otro tema que se trata en este trabajo es el efecto de la temperatura en los flujos viscoelásticos, donde se considerará un acople bidireccional con el problema térmico. Por un lado, ahora las propiedades del fluido dependen de la temperatura, y por otro, en la ecuación de energía tenemos que considerar la disipación viscosa como fuente térmica. Este estudio es interesante debido a que los fluidos viscoelásticos son sometidos a altas temperaturas en muchas aplicaciones industriales. Por otra parte, también se explora la incorporación de subescalas dependientes del tiempo en el método de estabilización. Este cambio será crucial para paliar dos tipos de problemas: el primero relacionado con la inestabilidad que se produce cuando resolvemos discretizaciones anisotropicas espacio-tiempo, y la segunda para tratar con el mencionado crecimiento exponencial que aparece cuando los flujos viscoelásticos tienen alto número de Weissenberg. Esta estrategia se aplica tanto a la formulación estándar de las ecuaciones como a la logaritmica. Finalmente, como la computación de la formulación logaritmica es cara computacionalmente, sobre todo cuando el esquema es de tipo monolítico, se ha diseñado un esquema de paso fraccionado en que el sistema de ecuaciones para esta formulación se desacopla. Este algoritmo resulta especialemnte útil para capturar inestabilidades púramente elásticas. Estas inestabilidades pueden desembocar en turbulencia elástica, que es un fenómeno físico en que el flujo se vuelve caótico a pesar de contar con un bajo número de Reynolds.