Acute myeloid leukemia (AML) is an aggressive disease with suboptimal overall survival, especially in relapsed/refractory patients. The primary goal of salvage therapy in this patient is to achieve optimal disease control, thereby allowing the transition to hematopoietic stem cell transplantation (HSCT), which remains the only curative option for a subset of these patients. Allogeneic KIR ligand-mismatched CD56+ NK/NKT-like cells have demonstrated antileukemic activity and represent a promising platform for the development of novel cellular therapies.

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.

Human neural progenitor cells (hNPCs) show promise in slowing retinal degeneration and are currently being tested in clinical trials for retinitis pigmentosa (RP). However, the long-term fate of grafted hNPCs and their interaction with host retinal cells remain unclear. Here, we used single-cell transcriptomics to investigate temporal gene expression changes in grafted hNPCs and host retinal cells following subretinal injection into a rodent model of RP, revealing dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs primarily differentiate into an astroglial phenotype and mature over time, contributing to photoreceptor protection through trophic factor secretion, metabolic modulation, suppression of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a decline in intercellular signaling and communication strength over time, correlating with weakened hNPC-host interactions. These findings suggest that enhancing trophic factor support, particularly MANF, and improving the host retinal environment are critical for sustaining long-term vision preservation.

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.

The Management of Myelomeningocele Study (MOMS) trial established the benefit of in-utero repair of myelomeningocele, with a decreased need for ventriculoperitoneal shunt placement. However, although there was some improvement of motor function, over half of the patients were unable to ambulate independently. Live placenta-derived mesenchymal stem cells (PMSCs) seeded on an extracellular matrix have shown promise in rescuing neurological function in the fetal ovine model of myelomeningocele. We aimed to evaluate the safety of this novel, living, stem cell product to augment the prenatal repair of myelomeningocele.

This pilot clinical study aimed to develop and validate standardized manufacturing and quality control procedures for autologous skeletal muscle-derived (SkM-MSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs), and to explore the feasibility, safety and preliminary efficacy of periurethral injection of these products in women with stress urinary incontinence (SUI).

This phase I clinical trial evaluated the safety and preliminary efficacy of three intra-articular injections of 20 × 106 allogeneic Umbilical Cord-derived Mesenchymal Stromal Cells (UC-MSCs) in patients with Knee Osteoarthritis (OA) at a two-month interval.

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.

Natural killer T (NKT) cells show intense tumor-killing activity through direct and indirect pathways. However, humans have less than 0.01% of NKT cells in the peripheral blood, making it difficult to apply NKT cells for cancer treatment. We have successfully produced invariant NKT cells derived from induced pluripotent stem cells (iPSC-iNKT cells) and demonstrated the tolerability of this product in a previous phase 1 clinical trial. Although the iPSC-iNKT cells showed substantial anti-tumor activity against various tumor cell types when combined with α-Galactosylceramide-pulsed autologous dendritic cells (DC/Gal) in non-clinical experiments, the tolerability of this combination therapy for humans has not demonstrated yet. Thus, we planned this first-in-human phase 1 open-label clinical trial to demonstrate data on tolerability and safety, as well as explore the immunological changes that occur following this combination treatment. We hypothesize that the sequential induction of nasal submucosal DC/Gal injection and intra-arterial administration of the iPSC-iNKT cells is tolerable and has a favorable safety profile for cancer patients. This trial provides vital and fundamental information for next-phase clinical trials and future applications of iPSC-iNKT cells for various cancer patients (jRCTa030220741; URL: https://jrct.mhlw.go.jp/en-latest-detail/jRCTa030220741).

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.

Mesenchymal stem cells (MSCs) hold substantial promise in regenerative medicine owing to their immunomodulatory, neuroregenerative, and self-renewal properties. Adipose tissue (AT) serves as an optimal MSC source due to its high yield and rapid proliferation. This study evaluated the safety and exploratory clinical effects of non-cryopreserved, culture-expanded autologous AT-MSCs in patients with secondary progressive multiple sclerosis (SPMS).

Cystinosis is a multisystemic lysosomal storage disorder caused by pathogenic variants in CTNS, the gene encoding cystinosin, a lysosomal transmembrane cystine transporter. In patients with cystinosis, cystine accumulates within lysosomes in all organs. The cystine-depleting agent cysteamine delays but does not prevent disease progression.

Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel.

A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.

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.

Latent Epstein-Barr virus (EBV) infection is asymptomatic in most adults but can be associated with lymphoma, particularly in immunocompromised patients. Options are limited for patients with EBV viremia disease refractory to B-cell depleting antibodies or chemotherapy. Cellular therapies targeting EBV have shown promise in treating EBV-associated malignancies and restoring anti-EBV immunity.