Lactate: an alternative pathway for the immunosuppressive properties of mesenchymal stem/stromal cells.

BACKGROUND: The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. MATERIALS AND METHODS: Murine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). RESULTS: Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%. CONCLUSION: These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.

Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.

Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.

An Expansion of the Endoplasmic Reticulum that Halts Autophagy is Permissive to Genome Instability.

The links between autophagy and genome stability, and whether they are important for lifespan and health, are not fully understood. We undertook a study to explore this notion at the molecular level using Saccharomyces cerevisiae. On the one hand, we triggered autophagy using rapamycin, to which we exposed mutants defective in preserving genome integrity, then assessed their viability, their ability to induce autophagy and the link between these two parameters. On the other hand, we searched for molecules derived from plant extracts known to have powerful benefits on human health to try to rescue the negative effects rapamycin had against some of these mutants. We uncover that autophagy execution is lethal for mutants unable to repair DNA double strand breaks, while the extract from Silybum marianum seeds induces an expansion of the endoplasmic reticulum (ER) that blocks autophagy and protects them. Our data uncover a connection between genome integrity and homeostasis of the ER whereby ER stress-like scenarios render cells tolerant to sub-optimal genome integrity conditions.

Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment.

Osteoarticular diseases (OD), such as rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic autoimmune/inflammatory and age-related diseases that affect the joints and other organs for which the current therapies are not effective. Cell therapy using mesenchymal stem/stromal cells (MSCs) is an alternative treatment due to their immunomodulatory and tissue differentiation capacity. Several experimental studies in numerous diseases have demonstrated the MSCs' therapeutic effects. However, MSCs have shown heterogeneity, instability of stemness and differentiation capacities, limited homing ability, and various adverse responses such as abnormal differentiation and tumor formation. Recently, acellular therapy based on MSC secreted factors has raised the attention of several studies. It has been shown that molecules embedded in extracellular vesicles (EVs) derived from MSCs, particularly those from the small fraction enriched in exosomes (sEVs), effectively mimic their impact in target cells. The biological effects of sEVs critically depend on their cargo, where sEVs-embedded microRNAs (miRNAs) are particularly relevant due to their crucial role in gene expression regulation. Therefore, in this review, we will focus on the effect of sEVs derived from MSCs and their miRNA cargo on target cells associated with the pathology of RA and OA and their potential therapeutic impact.

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis.

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models-S. cerevisiae, five cancer cell lines, and the parasite L. mexicana-were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.