Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a “galaxy” of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of “Exogenous Restitution of Intercellular Signalling of Stem Cells” (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.

Inflammatory bowel diseases (IBD) are an example of chronic diseases affecting 40% of the population, which involved tissue damage and an inflammatory process not satisfactorily controlled with current therapies. Data suggest that mesenchymal stem cells (MSC) may be a therapeutic option for these processes, and especially for IBD, due to their multifactorial approaches such as anti-inflammatory, anti-oxidative stress, anti-apoptotic, anti-fibrotic, regenerative, angiogenic, anti-tumor, or anti-microbial. However, MSC therapy is associated with important limitations as safety issues, handling difficulties for therapeutic purposes, and high economic cost. MSC-derived secretome products (conditioned medium or extracellular vesicles) are therefore a therapeutic option in IBD as they exhibit similar effects to their parent cells and avoid the issues of cell therapy. In this review, we proposed further studies to choose the ideal tissue source of MSC to treat IBD, the implementation of new standardized production strategies, quality controls and the integration of other technologies, such as hydrogels, which may improve the therapeutic effects of derived-MSC secretome products in IBD.

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P₀) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.

Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.

Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFNβ, and NFĸB in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs’ expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior.

Recent investigations point at the stromal microenvironment to assess additional diagnostic information and provide new therapeutic targets in cancer. The aim of the study was to contribute to the characterization of the phenotype of cancer-associated fibroblasts (CAFs) in prostate cancer (PCa) compared with normal prostate-associated fibroblasts (NAFs) and fibroblasts from benign prostatic hyperplasia (BPH). Three patient populations were prospectively recruited: 23 patients with new localized PCa, 14 patients with advanced PCa treated with androgenic deprivation therapy (ADT), and 7 patients with BPH. Gene expression of 20 stroma-derived factors, including the androgen receptor (AR), chaperones (HSPA1A and HSF1), growth factors (FGF2, FGF7, FGF10, HGF, PDGFB, and TGFβ), proteins implicated in invasion (MMP2, MMP9, and MMP11), inflammation (IL6, IL17RB, NFκB, and STAT3), and in-stroma/epithelium interaction (CDH11, CXCL12, CXCL14, and FAP), was evaluated. Localized PCa CAFs showed a significant higher expression of FGF7, IL6, MMP2, and MMP11 compared with NAFs or IL17RB compared with BPH fibroblasts, but significantly lower expression of FGF10 and IL17RB compared with NAFs or CXCL14 compared with BPH fibroblasts. In addition, CAFs from ADT-resistant PCa showed significantly higher MMP11 and NFκB but significant lower TGFβ expression compared with CAFs from ADT-sensitive tumors. Our results contribute to defining the CAFs phenotypes associated to PCa progression, which may contribute to the diagnosis and design of alternative therapies in PCa.