Knee osteoarthritis (OA) is a leading cause of pain and disability. Although conventional treatments show modest benefits, pilot and phase I/II trials with bone marrow (BM) and adipose‐derived (AD) mesenchymal stromal cells (MSCs) point to the feasibility, safety, and occurrence of clinical and structural improvement in focal or diffuse disease. This study aimed to assess the safety and efficacy of the intra‐articular injection of single or repeated umbilical cord‐derived (UC) MSCs in knee OA. UC‐MSCs were cultured in an International Organization for Standardization 9001:2015 certified Good Manufacturing Practice‐type Laboratory. Patients with symptomatic knee OA were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8), single‐dose (20 × 106) UC‐MSC at baseline (MSC‐1, n = 9), or repeated UC‐MSC doses at baseline and 6 months (20 × 106 × 2; MSC‐2, n = 9). Clinical scores and magnetic resonance images (MRIs) were assessed throughout the 12 months follow‐up. No severe adverse events were reported. Only MSC‐treated patients experienced significant pain and function improvements from baseline (p = .001). At 12 months, Western Ontario and Mc Master Universities Arthritis Index (WOMAC‐A; pain subscale) reached significantly lower levels of pain in the MSC‐2‐treated group (1.1 ± 1.3) as compared with the HA group (4.3 ± 3.5; p = .04). Pain Visual Analog scale was significantly lower in the MSC‐2 group versus the HA group (2.4 ± 2.1 vs. 22.1 ± 9.8, p = .03) at 12 months. For total WOMAC, MSC‐2 had lower scores than HA at 12 months (4.2 ± 3.9 vs. 15.2 ± 11, p = .05). No differences in MRI scores were detected. In a phase I/II trial (NCT02580695), repeated UC‐MSC treatment is safe and superior to active comparator in knee OA at 1‐year follow‐up. Stem Cells Translational Medicine 2019;8:215&224

While mesenchymal stem cells (MSCs)-based therapy appears to be promising, there are concerns regarding possible side effects related to the unwanted suppression of antimicrobial immunity leading to an increased risk of infection. Conversely, recent data show that MSCs exert strong antimicrobial effects through indirect and direct mechanisms, partially mediated by the secretion of antimicrobial peptides and proteins (AMPs). In fact, MSCs have been reported to increase bacterial clearance in preclinical models of sepsis, acute respiratory distress syndrome, and cystic fibrosis-related infections. This article reviews the current evidence regarding the direct antimicrobial effector function of MSCs, focusing mainly on the role of MSCs-derived AMPs. The strategies that might modulate the expression and secretion of these AMPs, leading to enhanced antimicrobial effect, are highlighted. Furthermore, studies evaluating the presence of AMPs in the cargo of extracellular vesicles (EVs) are underlined as perspective opportunities to develop new drug delivery tools. The antimicrobial potential of MSCs-derived EVs can also be heightened through cell conditioning and/or drug loading. Finally, improving the pharmacokinetics and delivery, in addition to deciphering the multi-target drug status of AMPs, should synergistically lead to key advances against infections caused by drug-resistant strains.

IntroductionSepsis is a clinical syndrome associated with a severe systemic inflammation induced by infection. Although different anti-microbial drugs have been used as treatments, morbidity and mortality rates remain high. Mesenchymal stem cells (MSCs) derived from the bone marrow have demonstrated a partial protective effect in sepsis. Menstrual derived MSCs (MenSCs) emerge as an attractive candidate because they present important advantages over other sources, including improved proliferation rates and paracrine response under specific stress conditions. Here, we evaluate their therapeutic effect in a polymicrobial severe sepsis model.MethodsThe antimicrobial activity of MenSCs was determined in vitro through direct and indirect bacterial growth assays and the measurement of the expression levels of different antimicrobial peptides (AMPs) by quantitative reverse transcription-polymerase chain reaction. The therapeutic effect of MenSCs was determined in the cecal ligation and puncture (CLP) mouse model. Mice were then treated with antibiotics (AB) or MenSCs alone or in combination. The survival rates and histological and biochemical parameters were evaluated, and the systemic levels of pro- and anti-inflammatory cytokines as well as the response of specific lymphocyte subsets were determined by flow cytometry.ResultsMenSCs exerted an important antimicrobial effect in vitro, mediated by a higher expression of the AMP-hepcidin. In the CLP mouse model, MenSCs in synergy with AB (a) improved the survival rate (95 %) in comparison with saline (6 %), AB (73 %), and MenSCs alone (48 %) groups; (b) enhanced bacterial clearance in the peritoneal fluids and blood; (c) reduced organ injuries evaluated by lower concentrations of the liver enzymes alanine aminotransferase and aspartate aminotransferase; and (d) modulated the inflammatory response through reduction of pro- and anti-inflammatory cytokines without significant loss of T and B lymphocytes.ConclusionsWe conclude that MenSCs in combination with AB enhance survival in CLP-induced sepsis by acting on multiples targets. MenSCs thus constitute a feasible approach for the future clinical treatment of sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0192-0) contains supplementary material, which is available to authorized users.

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IntroductionStem cells isolated from menstrual fluid (MenSCs) exhibit mesenchymal stem cell (MSCs)-like properties including multi-lineage differentiation capacity. Besides, menstrual fluid has important advantages over other sources for the isolation of MSCs, including ease of access and repeated sampling in a noninvasive manner. Such attributes allow the rapid culture of MenSCs in numbers that are sufficient for therapeutical doses, at lower cell passages.MethodsIn this study, we advance the characterization of MenSC populations in comparison to bone marrow derived mesenchymal stem cells (BM-MSCs) with regards to proliferation, lineage differentiation, migration potential, secretion profile and angiogenic properties in vitro and in a matrigel plug assay in mice. We additionally tested their ability to support hematopoietic stem cell (HSC) expansion in vitro.ResultsThe phenotypic analysis of MenSCs revealed a profile largely similar to the BM-MSCs with the exception of a higher expression of the adhesion molecule CD49a (alpha1-integrin). Furthermore, the fibroblast colony forming units (CFU-F) from MenSCs yielded a 2 to 4 fold higher frequency of progenitors and their in vitro migration capacity was superior to BM-MSCs. In addition, MenSCs evidenced a superior paracrine response to hypoxic conditions as evidenced by the secretion of vascular endothelial growth factor and basic fibroblast growth factor and also improved angiogenic effect of conditioned media on endothelial cells. Furthermore, MenSCs were able to induce angiogenesis in a matrigel plug assay in vivo. Thus, an 8-fold increase in hemoglobin content was observed in implanted plugs containing MenSCs compared to BM-MSCs. Finally, we demonstrated, for the first time, the capacity of MenSCs to support the ex-vivo expansion of HSCs, since higher expansion rates of the CD34 + CD133+ population as well as higher numbers of early progenitor (CFU-GEMM) colonies were observed in comparison to the BM source.ConclusionsWe present evidence showing superiority of MenSCs with respect to several functional aspects, in comparison with BM-MSCs. However, the impact of such properties in their use as adult-derived stem cells for regenerative3 medicine remains to be clarified.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0013-5) contains supplementary material, which is available to authorized users.

Menstrual-derived stem cells (MenSCs) are a new source of mesenchymal stem cells isolated from the menstrual fluid. Currently, there is a growing interest in their clinical potential due to fact that they are multipotent, highly proliferative, and easy to obtain in a non-invasive manner. Sampling can be repeated periodically in a simplified and reproducible manner devoid of complications that no existing cell source can match. MenSCs are also free of ethical dilemmas, and display novel properties with regard to presently known adult derived stem cells. This review details their distinctive biological properties regarding immunophenotype and function, proliferation rate, differentiation potential, and paracrine effects mediated by secreted factors. Their possible role in antenatal diagnosis is also discussed. While more insight on their immunomodulatory and diagnostic properties is needed, the impact of clinical and epidemiological factors, such as age, use of contraceptives, or hormonal status still requires further investigations to properly assess their current and future use in clinical application and diagnosis.

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Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies.