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

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher’s exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

Nitric oxide (NO) is an intracellular messenger in several cell systems, but its contribution to embryonic stem cell (ESC) biology has not been characterized. Exposure of ESCs to low concentrations (2–20 μM) of the NO donor diethylenetriamine NO adduct confers protection from apoptosis elicited by leukaemia inhibitory factor (LIF) withdrawal. NO blocked caspase 3 activation, PARP degradation, downregulation of the pro-apoptotic genes Casp7, Casp9, Bax and Bak1 and upregulation of the anti-apoptotic genes Bcl-2 111, Bcl-2 and Birc6. These effects were also observed in cells overexpressing eNOS. Exposure of LIF-deprived mESCs to low NO prevented the loss of expression of self-renewal genes (Oct4, Nanog and Sox2) and the SSEA marker. Moreover, NO blocked the differentiation process promoted by the absence of LIF and bFGF in mouse and human ESCs. NO treatment decreased the expression of differentiation markers, such as Brachyury, Gata6 and Gata4. Constitutive overexpression of eNOS in cells exposed to LIF deprivation maintained the expression of self-renewal markers, whereas the differentiation genes were repressed. These effects were reversed by addition of the NOS inhibitor L-NMMA. Altogether, the data suggest that low NO has a role in the regulation of ESC differentiation by delaying the entry into differentiation, arresting the loss of self-renewal markers and promoting cell survival by inhibiting apoptosis.

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