Beatriz G. Gálvez

Altered metabolic and stemness capacity of adipose tissue-derived stem cells from obese mouse and human.

Adipose stem cells (ASCs) are an appealing source of cells for therapeutic intervention; however, the environment from which ASCs are isolated may impact their usefulness. Using a range of functional assays, we have evaluated whether ASCs isolated from an obese environment are comparable to cells from non-obese adipose tissue. Results showed that ASCs isolated from obese tissue have a reduced proliferative ability and a loss of viability together with changes in telomerase activity and DNA telomere length, suggesting a decreased self-renewal capacity. Metabolic analysis demonstrated that mitochondrial content and function was impaired in obese-derived ASCs resulting in changes in favored oxidative substrates. These findings highlight the impact of obesity on adult stem properties. Hence, caution should be exercised when considering the source of ASCs for cellular therapies since their therapeutic potential may be impaired.

‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue

The increasing ageing of our societies is accompanied by a pandemic of obesity and related cardiometabolic disorders. Progressive dysfunction of the white adipose tissue is increasingly recognized as an important hallmark of the ageing process, which in turn contributes to metabolic alterations, multi‐organ damage and a systemic pro‐inflammatory state (‘inflammageing’). On the other hand, obesity, the paradigm of adipose tissue dysfunction, shares numerous biological similarities with the normal ageing process such as chronic inflammation and multi‐system alterations. Accordingly, understanding the interplay between accelerated ageing related to obesity and adipose tissue dysfunction is critical to gain insight into the ageing process in general as well as into the pathophysiology of obesity and other related conditions. Here we postulate the concept of ‘adipaging’ to illustrate the common links between ageing and obesity and the fact that, to a great extent, obese adults are prematurely aged individuals.

Low-Intensity Pulsed Ultrasound Improves the Functional Properties of Cardiac Mesoangioblasts

Cell-based therapy is a promising approach for many diseases, including ischemic heart disease. Cardiac mesoangioblasts are committed vessel-associated progenitors that can restore to a significant, although partial, extent, heart structure and function in a murine model of myocardial infarction. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive form of mechanical energy that can be delivered into biological tissues as acoustic pressure waves, and is widely used for clinical applications including bone fracture healing. We hypothesized that the positive effects of LIPUS on bone and soft tissue, such as increased cell differentiation and cytoskeleton reorganization, could be applied to increase the therapeutic potential of mesoangioblasts for heart repair. In this work, we show that LIPUS stimulation of cardiac mesoangioblasts isolated from mouse and human heart results in significant cellular modifications that provide beneficial effects to the cells, including increased malleability and improved motility. Additionally, LIPUS stimulation increased the number of binucleated cells and induced cardiac differentiation to an extent comparable with 5′-azacytidine treatment. Mechanistically, LIPUS stimulation activated the BMP-Smad signalling pathway and increased the expression of myosin light chain-2 together with upregulation of β1 integrin and RhoA, highlighting a potentially important role for cytoskeleton reorganization. Taken together, these results provide functional evidence that LIPUS might be a useful tool to explore in the field of heart cell therapy.

Adipose stem cells from obese patients show specific differences in the metabolic regulators vitamin D and Gas5

Adipose tissue is a significant source of mesenchymal stem cells for regenerative therapies; however, caution should be taken as their environmental niche can affect their functional properties. We have previously demonstrated the negative impact of obesity on the function of adipose-derived stem cells (ASCs). Here we have evaluated other possible properties and targets that are altered by obesity such as the recently described long non-coding molecule Gas5, which is involved in glucocorticoid resistance. Using ASCs isolated from obese (oASCs) and control subjects (cASCs), we have analyzed additional metabolic and inflammatory conditions that could be related with their impaired therapeutic potential and consequently their possible usefulness in the clinic.

Circulating leptin and adiponectin concentrations in healthy exceptional longevity.

People reaching exceptional longevity free of major age-related diseases represent the paradigm of successful aging. Adipose tissue function declines as we age, potentially resulting in changes of circulating adipokines (e.g., leptin and adiponectin). Here, we measured circulating levels of leptin and adiponectin in healthy centenarians (n=81; 100-104 years) and younger elderly controls (n=46; 70-80 years). Centenarians had significant higher serum levels of leptin compared with controls (p<0.001), whereas no significant differences were observed for adiponectin. Further research including also other blood variables will be needed to elucidate whether high leptin levels could serve as a hallmark of healthy exceptional longevity.

Biological Rationale for Regular Physical Exercise as an Effective Intervention for the Prevention and Treatment of Depressive Disorders

Depression is a major medical and social problem. Here we review current body of knowledge on the benefits of exercise as an effective strategy for both the prevention and treatment of this condition. We also analyze the biological pathways involved in such potential benefits, which include changes in neurotrophic factors, oxidative stress and inflammation, telomere length, brain volume and microvessels, neurotransmitters or hormones. We also identify major caveats in this field of research: further studies are needed to identify which are the most appropriate types of exercise interventions (intensity, duration, or frequency) to treat and prevent depression.

Membrane Blebbing Is Required for Mesenchymal Precursor Migration.

Mesenchymal precursors (MPs) present some advantageous features, such as differentiation and migration, which make them promising candidates for cell therapy. A better understanding of MP migration characteristics would aid the development of cell delivery protocols. Traditionally, cell migration is thought to occur only through the formation of lamellipodia. More recently, contractility-driven bleb formation has emerged as an alternative mechanism of motility. Here we report that MPs derived from different tissues present spontaneously dynamic cytoplasmic projections in sub-confluent culture, which appear as a combination of lamellipodia with blebs in the leading edge. Upon initial seeding, however, only bleb structures could be observed. Immunofluorescence revealed the presence of pERM, RhoA and F-actin during the blebbing process. Results from migration assays in the presence of blebbistatin, a myosin II inhibitor, showed that bleb formation correlated with migratory capacity, suggesting a functional role for blebs in migration. Bleb formation might be a useful mechanism to improve cell migration in cellular therapy protocols.

Muscle molecular adaptations to endurance exercise training are conditioned by glycogen availability: a proteomics‐based analysis in the McArdle mouse model

Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate‐intensity endurance exercise training regime. Yet, they fail to reach the performance capacity of healthy mice with normal glycogen availability. There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability. Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild‐type mice: LIMCH1, PARP1 and TIGD4. In turn, trained McArdle mice presented strong expression of mitogen‐activated protein kinase 12 (MAPK12).

Functional Assays of Stem Cell Properties Derived from Different Niches

It has been described that adult tissues contain mesenchymal stem cell populations. The specific areas where stem cells reside are known as niches. Crosstalk between cells and their niche is essential to maintain the correct functionality of stem cell. MSCs present a set of abilities such as migration, invasion, and angiogenic potentials, which make them ideal candidates for cell-based therapies. In order to test the regenerative capacity of these cells, we have described a methodology for the collection and for the evaluation of these mesenchymal precursors from different niches.