Despite advances in the development of mesenchymal stem cells (MSCs), the ultimate benefits of MSCs against current cell-based therapies are still limited. This study aimed to assess the safety, feasibility, and efficacy of Cytopeutics® umbilical cord-derived MSCs (Chondrocell-EX) in patients with knee cartilage injury.

The safety of multi-dose mesenchymal stem cell (MSC) regimens has seldom been systematically investigated. The PRIME-HFrEF (Prospective Randomized Controlled Study of Multiple Intravenous Infusions of Umbilical Cord-derived MSCs in Patients with Heart Failure and Reduced Ejection Fraction) trial was a single-center, randomized, placebo-controlled, investigator-initiated study (ClinicalTrials.gov identifier: NCT04992832) that enrolled 40 patients. The trial aimed to evaluate the safety of three intravenous infusions of Umbilical Cord-derived MSCs (UC-MSCs) administered at six-week intervals in patients with heart failure and reduced ejection fraction (HFrEF), while also collecting exploratory efficacy data. The primary safety endpoint was the incidence of serious adverse events (SAEs), and the primary efficacy endpoint was the change (Δ) in left ventricular ejection fraction (LVEF). Secondary efficacy endpoints included changes in right ventricular (RV) end-systolic and end-diastolic volumes (ESV and EDV). Thirty-nine patients completed 12 study visits over a 360-day follow-up period or until death. The incidence of SAEs did not differ significantly between treatment groups. However, UC-MSC-treated patients exhibited elevated D-dimer levels, suggesting a treatment-associated increase in coagulability. D-dimer levels were negatively correlated with LVEF, and no significant difference in ΔLVEF was observed between groups. In contrast, the improvement in ΔRVESV was significantly greater in the UC-MSC group than in placebo-treated patients (P = 0.033). In summary, multi-dose UC-MSC infusions were safely administered to patients with HFrEF and were associated with improvements in RV volumes. However, these benefits were accompanied by transient increases in coagulability, which may have attenuated potential improvements in left ventricular contractile function.

To compare the effect of mesenchymal stem cell (MSC) infusion vs. placebo on glomerular filtration rate (GFR) in patients with stage II-IV diabetic nephropathy.

Frailty, a syndrome that decreases healthspan in older individuals, lacks effective therapies. We conducted a randomized, dose-finding clinical trial to test whether human bone marrow-derived allogeneic mesenchymal stem cells (MSCs; laromestrocel) improve physical functioning and patient self-reported outcomes in ambulatory individuals with frailty (ClinicalTrials.gov #NCT03169231; N = 148). Laromestrocel infusion results in clinically meaningful, dose- and time-dependent increases in the 6-min walk test (6MWT; primary endpoint) compared with placebo: 63.4 m (95% confidence interval [CI]: 17.1-109.6 m; p = 0.0077) at month 9 and 41.3 m (95% CI: -2.4-84.9 m; p = 0.0635) at month 6. Increased 6MWT distance correlates with PROMIS Physical Function score, and increasing doses of laromestrocel are associated with decreases in soluble (degraded) tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE2), the cognate receptor for the angiopoietins, identifying a potential biomarker of laromestrocel responsiveness. These findings identify a stem cell therapy approach for the management of patients with hypomobility and other features of aging frailty.

The study aimed to investigate the effects of 5 weeks of post-exercise cold-water immersion (CWI) following high-intensity interval training (HIIT) sessions on the satellite cell pool, muscle content of inflammatory markers, muscle expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), maximal oxygen uptake (V̇O2max), and running performance. Sixteen healthy males completed baseline assessments, including muscle biopsies, a graded exercise test for V̇O2max determination, and a constant work-rate (CWR) running test to assess time to task failure (TTF). Participants were ranked according to V̇O2max and randomly allocated to either a training-only control group (n = 7) or a CWI group (n = 9), which underwent CWI (11.2°C ± 0.2°C for 15 min) following each HIIT session. The HIIT program consisted of three weekly sessions 5-8 × 2-min bouts at 95% V̇O2max. At the end of weeks four and five, all participants repeated the same sequence of assessments. Training increased V̇O2max values, TTF at CWR, satellite cell pool, PGC-1α content, and induced changes in muscle morphology (connective tissue), as indicated by a main effect of time (p ≤ 0.031); none of the analyzed variables showed a main effect of condition (p ≥ 0.098) or interaction (p ≥ 0.088). No significant alterations were observed in inflammatory markers over time (p ≥ 0.395) and condition (p ≥ 0.115). In conclusion, 5 weeks of post-exercise CWI following HIIT did not influence the satellite cell pool, muscle inflammation status, muscle PGC-1α content, muscle morphological, V̇O2max, or running performance.

Modifiable health behaviors such as exercise regulate adiposity in adults, but the effects of exercise during pregnancy on infant adiposity remain understudied. This report analyzed the relationship between prenatal exercise frequency, intensity, time, type, and volume (FITT-V) and infant adiposity, to better guide prenatal exercise prescription. Female participants [body mass index = 29.0 kg/m2, 30.5 yr of age, with gravida = 1 and parity = 0, peak oxygen consumption (V̇o2peak) = 21.9 mL/kg/min, and pregnant for 39.6 wk] were randomized to supervised exercise (aerobic, resistance, combination) or attention control for ∼24 wk during pregnancy. FITT-V metrics were analyzed from session records. Infant mesenchymal stem cells (MSCs), a model of infant adiposity, were collected from umbilical cord at delivery, adipogenically differentiated, and stained for lipids. Infant body fat percentage was estimated from skinfolds measured at 1 mo of age. Higher weekly exercise volume correlated with lower infant body fat (R2 = 0.12, P = 0.03) and MSC lipids (R2 = 0.13, P = 0.01). Weekly exercise frequency (R2 = 0.06, P = 0.10) and total volume (R2 = 0.19, P = 0.002) influenced adiposity. Subscapular skinfolds were notably affected by exercise (R2 = 0.27, P < 0.001). We conclude that in utero exposure to exercise beyond minimum recommendations is associated with reduced infant adiposity. Specifically, our findings suggest that exercising below 450 metabolic equivalent (MET)·min/wk, e.g., exercising at an average of 3 METs for 150 min/wk or 5 METs for 90 min/wk, excludes individuals from these offspring health benefits.NEW & NOTEWORTHY This study was the first to test how specific prenatal exercise dose, i.e., the FITT-V (frequency, intensity, time, type, volume) metrics, could influence the storage of triglycerides in infant adipogenic mesenchymal stem cells (MSCs). Prenatal exercise led to a reduction in infant whole body fat percentage (BF%), which was reflected by lower lipid storage in infant MSCs. Changes in lipid content were observed in offspring born to participants exercising beyond the minimum recommended weekly volume, 450 metabolic equivalent (MET)·min/wk.

Prenatal exercise decreases offspring adiposity, but it is uncertain whether this relationship is present in offspring exposed to obesity in utero. We aimed to determine whether exercise during pregnancy reduces infant cellular and whole-body adiposity in offspring born to women with obesity. This is a sub-analysis of a randomized controlled trial, where women were randomized to supervised exercise or control for ~24 weeks during pregnancy. Exercise FITT-V metrics (frequency, intensity, time, type, and volume) were collected. Infant mesenchymal stem cells (MSCs) (healthy weight [n = 16], obesity [n = 21]) were adipogenically differentiated and stained for lipid content. Infant body composition was measured at 1 month of age via skinfold. Among women randomized to control, maternal BMI influenced infant adiposity; infants exposed to obesity had higher body fat percentage (p = 0.02). Birthweight was negatively correlated with infant body fat; offspring with lower birthweight had higher body fat (R2 = 0.38, p = 0.03). Maternal weekly exercise volume trended toward negative association with infant body fat (R2 = 0.33, p = 0.06) and lipid content (R2 = 0.21, p = 0.06). For infants born to women with obesity, exercise during pregnancy helps reduce adiposity.

Temporomandibular joint osteoarthritis (TMJ-OA) is a progressive degenerative disorder, for which therapeutic interventions remain limited. The disruption of metabolic homeostasis plays a critical role in the pathogenesis and advancement of TMJ-OA. However, it remains unclear whether extracellular vesicles (EVs) as cellular metabolites are correlated with the pathogenesis, treatment and diagnosis of TMJ-OA. In this study, we demonstrated that autologous circulating extracellular vesicles (C-EVs) possessed significant therapeutic potential for TMJ-OA through the targeted removal of senescent chondrocytes. In a randomized clinical trial (ChiCTR2200063153), C-EV administration was found to significantly enhance condylar bone regeneration and alleviate symptoms relative to hyaluronic acid controls, without eliciting any adverse effects. Comparative analysis revealed that joint cavity-derived EVs from TMJ-OA patients (OA-EVs) exhibited structural abnormalities, diminished expression of canonical EV markers, and pro-inflammatory characteristics. In contrast, C-EVs were significantly enriched with functional proteins C1q binding protein (C1QBP). And the level of C1QBP-positive EVs was positively correlated with therapeutic outcomes, thereby establishing C1QBP as a potential predictive biomarker for TMJ-OA. Furthermore, C-EVs reestablished joint homeostasis by regulating the immune microenvironment and tissue regeneration capacity. Mechanistically, C1QBPhigh C-EVs upregulated the expression of membrane C1q on senescent chondrocytes, thereby initiating C1q-C1QBP binding, p14ARF translocation to mitochondria, and subsequent cytochrome C/caspase-3-dependent apoptosis. Our findings demonstrate that C-EVs serve a dual therapeutic role by facilitating the clearance of senescent cells via the C1QBP/C1q/p14ARF axis, while promoting tissue regeneration and regulating metabolites homeostasis, offering a novel biological strategy for TMJ-OA treatment.

Chronic kidney disease (CKD) poses a significant global health burden by reducing quality of life and increasing mortality. Current therapies remain inadequate in halting its progression, necessitating novel treatments to improve outcomes. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option. Phase I/II clinical trials evaluated the efficacy, safety, and tolerability of ELIXCYTE in slowing CKD progression. This multicenter, randomized, open-label study monitored estimated glomerular filtration rate (eGFR) changes over a 48-week period following a single intravenous infusion of ADSCs. Participants were allocated to one of three dosage groups, with primary outcomes assessing eGFR changes and secondary outcomes focusing on safety and tolerability. Results confirmed a favorable safety profile, with no dose-limiting toxicities observed in the low- and moderate-dose groups. Group-based trajectory modeling (GBTM) indicated that, overall, 88.24% of patients exhibited a trend of improvement or stabilization. In the low-dose group, 72.23% of patients demonstrated a stable trend, which was more consistent than in other dosage groups. Furthermore, patients with CKD stage 3B showed a numerically higher proportion of improving trajectories compared to those with stage 4 disease. The low-dose ADSC group exhibited a trend toward more favorable renal function trajectories and fewer adverse events than higher doses, suggesting that lower dosing may provide a balanced profile of safety and potential efficacy. However, despite the preliminary results indicating that ELIXCYTE may effectively slow CKD progression, further large-scale clinical trials are necessary to corroborate these findings and verify the efficacy of ADSC treatment.

Previous studies by the authors have shown that human amniotic membrane extract (AME) potentially improves epithelial damage in corneal and skin lesions. However, questions about its role in diabetic foot ulcer (DFU) treatment remain unanswered. In this study, patients with hard-to-heal DFUs were randomly selected after screening and, after confirming the safety of the AME in an initial selection of patients, the remaining participants were divided into two groups. The treatment group received an AME product (DiAMX, Royan Stem Cell Technology, Iran) (concentration 1mg/ml) with standard of care (SoC), topically, every 48 hours for the first week and then every 72 hours until complete closure. The control group received SoC. Patients were visited weekly, and any improvement, reduction in the wound area and any side-effects were recorded. The results of the safety phase (without the control group) showed that the AME had no adverse events. In the efficacy phase, there was no significant difference in baseline characteristics between the treatment and control groups. The results showed that the wound healing rate was 100% in the treatment group and 77.5±3.12% in the control group (p<0.0001) at week 6. All wounds (n=15) were closed in the treatment group and seven wounds had closed in the control group (p<0.0001). The findings of this study showed that the topical use of DiAMX, in addition to SoC, was patient-friendly, inexpensive, safe and effective in healing hard-to-heal DFUs.

To evaluate the osteogenic potential of dental pulp mesenchymal stem cells in extraction sockets of mandibular third molars by objective assessment of bone density and resorption.

Background and Objectives: MGN-3/Biobran (BRM4, Lentin Plus or Ribraxx) is a natural, rice bran-derived arabinoxylan immunoceutical that modulates the adaptive immune response to viral infections. In response to bacterial infections, basophils act as "first responders" and are also associated with modulation of the adaptive immune response. The maturation of pluripotent CD34+ stem cells into basophils is supported by the cytokine interleukin-3 (IL-3). The aim was to test the hypothesis that modulation of the adaptive immune response in bacterial infection by MGN-3/Biobran entails a basophilic response. The tick-related disorder Lyme borreliosis was chosen as the disease model; tick bites are associated with cutaneous IL-3-mediated basophil recruitment. Materials and Methods: A three-month randomised double-blind placebo-controlled trial was conducted in patients with a history of borreliosis who were suffering from symptoms attributable to this disorder. The immunoceutical group received oral Biobran; the dosage for both groups was 1 g thrice daily. Both groups were matched for age, sex, and ethnicity. Results: A higher percentage of basophil count occurred in the immunoceutical group (p = 0.038). The final general linear model included the group (immunoceutical/placebo) and change in fatigue assessed by the 11-item Chalder Fatigue Questionnaire (CFQ) (r2 = 0.63; p = 0.0066). The change in basophil count was positively correlated with CFQ change (rs = 0.633; p = 0.020); only the immunoceutical group showed a positive correlation. Conclusions: These results support the hypothesis being tested. Basophils may modulate the adaptive immune response by acting as immunoregulatory cells. They can regulate the functioning of type 2 T-helper lymphocytes, enhance immunological memory, and present antigens to CD8 T lymphocytes. Further studies are needed to clarify potential mechanistic factors and the timing of this basophilic response.

Cell therapy has been proposed as a promising treatment for neurological recovery in patients with stroke. However, a strategy to enhance its efficacy is needed, as its clinical benefits have not yet been demonstrated in clinical trials. This study evaluated the efficacy of combination therapy using allogeneic umbilical cord blood (UCB), a relatively safe therapeutic cell source, and recombinant human erythropoietin (rhEPO) in patients with subacute stroke.

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe type of epidermolysis bullosa resulting from mutations in COL7A1 gene. Patients experience various degrees of blistering following minor trauma which can over time lead to fibrosis, limb contractures and an increased risk of developing squamous cell carcinoma. The aim was to assess if repeated infusions of allogeneic umbilical cord derived mesenchymal stromal cells (UC-MSCs), CORDStromTM, were safe and could benefit children with RDEB. This was a prospective, double-blinded, randomised, placebo-controlled crossover trial with an internal dose de-escalation trial (for safety) conducted at the two National Paediatric UK EB centres in RDEB children aged >6months and <16years. Participants received IV infusions of 2-3 × 106 cells/kg of UC-MSCs or placebo at day 0 and 14 days later with a 9-month wash out period between the opposite. Main outcomes were change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring index (EBDASI) and the Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (ISCOREB), wound clinical appearance, pain, itch, and quality of life at 3-months from infusion. Results will be discussed at the meeting. This is the largest study worldwide in children with RDEB. Administering cell therapy early and at regular intervals has the potential to reduce inflammation, effectively modulate disease activity, and lead to clinically meaningful and sustained improvements in disease progression and quality of life. An open-label study is planned and will help us further evaluate the long-term safety and outcomes of CORDStromTM infusions in children with RDEB.

Although research in cell-based therapy is expanding, little is known about patient experience in cell therapy trials to-date. This study explores the experience and attitudes of participants involved in the ASCOT randomized controlled trial, a long-term orthopedic study comparing different cell therapies for the treatment of knee articular cartilage defects.

To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Early phase studies suggested improved outcomes with Orca-T, an allogeneic T-cell immunotherapy that uses purified donor regulatory T cells to prevent GVHD with significantly less immunosuppression. This phase 3 trial randomized adult patients (N = 187) with acute leukemias or myelodysplastic syndrome undergoing myeloablative conditioning to receive either Orca-T with tacrolimus or a conventional allograft with tacrolimus and methotrexate (Tac/MTX), using granulocyte colony-stimulating factor-mobilized peripheral blood from HLA-matched donors. The primary end point was survival free from moderate-to-severe chronic GVHD (cGVHD; cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm than in Tac/MTX (hazard ratio, 0.26; 95% confidence interval, 0.14-0.47; P< .001). One-year estimates were as follows: cGFS was 78.0% with Orca-T vs 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe cGVHD was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray test P< .001); overall survival was 93.9% with Orca-T vs 83.1% with Tac/MTX (P = .12); GVHD-free and relapse-free survival was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P< .001), respectively; nonrelapse mortality (NRM) was 3.4% with Orca-T vs 13.2% with Tac/MTX (P = .03). Orca-T met the primary end point of improved survival free from cGVHD compared with Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Moreover, significantly less toxicity was observed with Orca-T patients, including fewer serious infectious complications and less NRM. This trial was registered at www.clinicaltrials.gov as NCT05316701.

There is controversy about the benefits of bone marrow mononuclear cells (BMMC) to improve left ventricular dysfunction (LVD) in patients with coronary artery disease. We sought to evaluate the safety, feasibility and efficacy of the intracoronary infusion of BMMC to improve left ventricular ejection fraction (LVEF) in patients with chronic total coronary artery occlusions (CTO).

Concurrent training is commonly associated with blunted muscle hypertrophy compared with resistance training alone, but the underlying physiological mechanisms remain unclear. This study aimed to investigate the acute and chronic effects of concurrent versus resistance training on muscle protein synthesis, satellite cell dynamics, myonuclear content, myogenic regulatory factor expression, muscle fiber hypertrophy, strength, and aerobic capacity. Nineteen previously untrained young men were randomly assigned to either concurrent or resistance training for 16 wk. Muscle biopsies were collected before and 48 h after a standardized exercise session at weeks 4 and 16. Samples were analyzed for myofibrillar protein synthesis via deuterium oxide incorporation, satellite cell content, myonuclear number, and gene expression. Strength, aerobic capacity, and muscle fiber cross-sectional area were measured at baseline and postintervention. Muscle protein synthesis increased 48 h postexercise at both weeks 4 and 16 (P = 0.0105), with no group differences. Satellite cell content increased over time in type II fibers only (P = 0.0021). Myonuclear number increased in both fiber types (type I: P = 0.0301 and type II: P = 0.0009), with higher values in type I fibers in the concurrent training group (P = 0.0027). MYF5 and MYF6 expression increased over time (P = 0.0141 and P = 0.034, respectively), and MYOD1 was elevated postexercise only in concurrent training (P = 0.0009). Type II fiber size increased (P = 0.016). Strength gains were greater in resistance training (P = 0.016), whereas aerobic capacity improved only in concurrent training (P < 0.001). Sixteen weeks of concurrent training did not inhibit molecular mechanisms associated with muscle hypertrophy in previously untrained individuals.NEW & NOTEWORTHY Sixteen weeks of concurrent training with long-interval HIIT preserved key molecular adaptations related to muscle hypertrophy, including protein synthesis, satellite cell activity, and gene expression. Both concurrent and resistance training increased type II fiber cross-sectional area, but only concurrent training improved V̇o2peak. Although strength gains were lower with concurrent training, molecular and cellular remodeling remained intact, supporting it as an effective strategy to enhance both muscle growth and aerobic fitness simultaneously.

Cytomegalovirus (CMV) reactivation remains a common and serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), often leading to significant morbidity and mortality in immunocompromised recipients. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as a promising immunotherapeutic approach to restore antiviral immunity and prevent CMV-related complications. This interim analysis of a randomized phase I-II clinical trial evaluates the safety and preliminary efficacy of prophylactic infusion of donor-derived CMV-CTLs administered early after allo-HSCT. Twenty adult allo-HSCT recipients were randomized 1:1 to receive either standard care (control group) or a single intravenous infusion of 10 million donor-derived CMV-CTLs per m2 of body surface area (intervention group) between days + 14 to + 21 post-transplant. The primary endpoint was safety, defined by infusion-related adverse events and incidence of acute graft-versus-host disease (aGvHD). Secondary endpoints included incidence and kinetics of CMV reactivation, measured by serial quantitative RT-PCR during the first 90 days post-transplant. Baseline characteristics were balanced between the two groups. No grade 3-5 adverse events were observed following CMV-CTL infusion. aGvHD grade II occurred in 30% of the intervention group versus 40% in controls. The incidence of CMV reactivation at 90 days was lower in the intervention group (52.00%) compared to controls (77.78%), although not statistically significant (P = 0.580). However, CMV viral loads were significantly lower over time in the intervention group (P = 0.028), suggesting a favorable antiviral effect of CMV-CTLs. Prophylactic infusion of donor-derived CMV-CTLs early after allo-HSCT appears safe and may reduce CMV reactivation and viral burden. These findings support the potential of CMV-CTLs as a novel immunotherapeutic strategy for CMV management in high-risk transplant recipients. Further validation in larger, multicenter trials is warranted.

Atopic dermatitis (AD) is a chronic skin condition affecting patients' well-being, but conventional treatments have limitations. Mesenchymal stem cells (MSCs) present a promising option for AD therapy, though large-scale clinical studies are scarce. This study aimed to assess the efficacy and safety of autologous adipose tissue-derived MSC (AtMSC) in moderate to severe AD refractory to conventional treatments.