To evaluate the feasibility, safety and efficacy of the cutaneous application of Bioengineered Artificial Mesenchymal Sheet (BAMS) in venous leg ulcers (VLUs) versus conventional treatment.

In this single-center, double-blinded, randomized controlled trial, we investigated whether human umbilical cord-derived mesenchymal stromal cells loaded collagen scaffolds (hUC-MSC/CS) could improve the cumulative live-birth rate (cLBR) in infertile women with refractory thin endometrium (RTE). We randomly assigned 25 subfertile women with RTE, in a 1:1 ratio, to receive hysteroscopic adhesiolysis and plowing plus either hUC-MSC/CS or saline/CS (control) for intrauterine implantation. Uterine fluid was collected on the embryo transfer day for RNA-sequencing to explore the potential mechanisms by which hUC-MSCs exert their effects. The primary outcome was the cLBR. Live births occurred in 3 out of 11 women in the hUC-MSC/CS group and in 1 out of 13 women in the control group (27.3% vs 7.7%; relative risk [RR], 3.55; 95% confidence interval [CI], 0.43 to 29.42; P = .30). The cumulative frequencies of clinical pregnancy were 5/11 and 1/13 in the hUC-MSC/CS group and control group, respectively (45.5% vs. 7.7%; RR, 5.91; 95% CI, 0.81-43.28; P = .06). Two of 11 participants developed urticaria in the hUC-MSC/CS group. Enrichment analysis showed that T-cell activation had the largest proportion in the biological process category. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that most genes were related to cytokine-cytokine receptor interaction. In conclusion, there was a non-significant trend toward a higher cLBR with hUC-MSC/CS compared to controls, potentially through the cytokine-cytokine receptor interaction pathway. hUC-MSCs appeared to be relatively safe in a 1-year follow-up. Therefore, this novel therapy can be proposed to patients with RTE.

Osteoarthritis (OA) is a degenerative joint disease that primarily affects older adults, characterized by cartilage degradation, synovitis, and osteophyte formation. Despite its prevalence, no medical treatment can reverse the joint cartilage degradation, leading many patients to undergo invasive procedures such as arthroplasty. Mesenchymal stem cells (MSCs), particularly those derived from adipose tissue, have emerged as a promising therapeutic approach due to their ability to differentiate into chondrocytes and potentially regenerate cartilage. While MSCs from bone marrow and umbilical cord have shown efficacy in treating OA, adipose-derived MSCs (ADMSC) are more accessible and cost-effective. This study aims to evaluate the safety and efficacy of allogeneic ADMSC in treating knee OA.

Umbilical cord mesenchymal stem cell-derived (UCMSC-derived) secretome is anti- apoptotic, anti-inflammatory, antifibrotic, angiogenic, and tissue-regenerating. Thus, it may treat systemic lupus erythematosus (SLE). The aim of this study was to investigate the impact of the UCMSC-derived secretome on SLE patients' disease activity, using Mexican systemic lupus erythematosus disease activity index (MEX-SLEDAI) score, complement (C3 and C4) levels, tumor necrosis factor-alpha (TNF-α), anti-double-stranded DNA (anti-dsDNA), and interleukin-6 (IL-6) levels. This double-blind randomized controlled trial investigated the efficacy and safety of UCMSC-derived secretome in SLE patients with moderate disease activity. A total of 29 female patients were randomized into two groups to receive weekly 1.5 cc intramuscular injections of UCMSC-derived secretome or placebo (0.9% NaCl) for six weeks. Disease activity was assessed using the MEX-SLEDAI score, C3 and C4 levels, pro-inflammatory cytokines (IL- 6 and TNF-α), and anti-dsDNA antibodies at baseline, Day 22, and Day 43. Results showed a significant reduction in MEX-SLEDAI scores in the secretome group compared to the placebo group (p < 0.05). Complement C3 levels significantly increased in the secretome group on Day 43, indicating improved immune homeostasis, while C4 levels did not show significant differences between groups. IL-6 and TNF-α levels showed decreasing trends in the secretome group. Anti-dsDNA levels exhibited a decreasing trend in the secretome group, though not statistically significant. Importantly, no severe adverse events were observed, underscoring the safety of the intervention. UCMSC-derived secretome demonstrated immunomodulatory and anti-inflammatory effects, reducing disease activity in SLE patients. These findings suggest its potential as a safe and effective adjunct therapy for SLE, although further studies with larger sample sizes and extended follow-up periods are needed to validate these results.

Neonatal hypoxic ischemic encephalopathy (nHIE) is a serious disease that causes severe and chronic neurological damage. Hypothermia therapy improves patients' outcomes albeit with some limitations, but combining it with treatment with cord blood cells (analogous to mesenchymal stem cells [MSCs]) reportedly improves its effectiveness. TEMCELL HS Inj. (Temcell), a human bone marrow-derived MSC product used for acute graft-versus-host disease, seems an appropriate candidate for this combination therapy. Therefore, we performed a randomized, parallel-group study to compare combined treatment with Temcell and hypothermia versus hypothermia therapy-alone to evaluate the safety and efficacy of Temcell in nHIE patients. The primary endpoint was treatment response defined as an overall developmental quotient of ≥ 85 at 18 months of age. Fourteen patients were enrolled and randomized, with 7 assigned to each group. Both groups had similar demographic characteristics and nHIE severity. Treatment response was observed in 4 of the 6 (66.7%) patients in the Temcell combination group, and in 4 of the 7 patients (57.1%) in the hypothermia therapy-alone group. No marked differences in safety profile were observed between the groups. These results indicate that the efficacy of Temcell combined with hypothermia is comparable to therapeutic hypothermia for patients with nHIE.Clinical Trial Registration: jRCT1080224818.

Aim: To determine the effectiveness of a multidisciplinary rehabilitation program (MRP), integrating mesenchymal stem cells (MSCs) therapy, acupuncture, physiotherapy and physical exercises, in improving the functional recovery in patients with combat-related injuries and chronic critical lower limb ischemia (CCLLI).

This phase 2 study evaluated the impact of pegfilgrastim, a single-dose, long-acting granulocyte colony-stimulating factor, on the steady-state mobilization of hematopoietic stem cells into peripheral blood in patients with multiple myeloma (MM) or malignant lymphoma (ML). Efficacy and safety, along with CD34-positive cell mobilization outcomes were assessed in patients with MM, who were randomly assigned to pegfilgrastim (n = 30) or daily filgrastim (n = 31), and ML (pegfilgrastim only, n = 13) cohorts. In the MM cohort, CD34-positive cell counts ≥ 2 × 106/kg were achieved in 100% of patients in the pegfilgrastim group and 96.7% in the filgrastim group (difference: 3.3%; 80% confidence interval: -0.9-7.5%), demonstrating the non-inferiority of pegfilgrastim to filgrastim. All patients in the ML cohort achieved ≥ 2 × 106/kg CD34-positive cell counts. The plerixafor administration rates in the MM cohort were 50.0% and 63.3% in the pegfilgrastim and filgrastim groups, respectively, and 91.7% in the ML cohort. There were no major differences in safety measures between the two groups. Although the sample size was small, particularly in the ML cohort, a single dose of pegfilgrastim demonstrated comparable efficacy and safety to daily doses of filgrastim, indicating its potential for clinical use while reducing patient burden.Trial Registration: jRCT2011210029, NCT05007652.

Intrathecal injection (IT) of autologous mesenchymal stem cells (MSC) showed robust beneficial effects a previous randomized study from our center, in patients with progressive multiple sclerosis (MS) (NCT02166021). We evaluated here the effect of repeated MSC-NG01 transplantations on serum biomarkers of neuroinflammation and neurodegeneration, namely, neurofilaments light chains (NFL) and glial fibrillary acidic protein (GFAP), in an open-label extension trial.

Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect haemopoietic stem and progenitor cells (HSPCs) for haemopoietic stem cell transplants (HSCT), however there is a clinical need to reduce collection times and achieve sufficient HSPC doses for successful engraftment. Short bouts of interval cycling transiently enrich peripheral blood with HSPCs and cytolytic natural killer (CD56dim NK) cells, which predict engraftment success and prevent post-transplant complications respectively. Despite this, feasible protocols for use during PBSC collections (≈ 3 h) have yet to be evaluated.

Adipose extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel) contains adipose-derived stem cells, extracellular matrix, and other cell components, and possesses the ability to promote collagen production and serve as a filling agent.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety and efficacy of laromestrocel, a bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD clinical progression, atrophy and neuroinflammation. Participants across ten centers in the United States were randomly assigned 1:1:1:1 to four infusion groups: group 1 (placebo; four monthly infusions, n = 12); group 2 (25 million cells, one infusion followed by three monthly infusions of placebo, n = 13); group 3 (25 million cells; four monthly doses, n = 13); and group 4 (100 million cells; four monthly doses, n = 11). The study met its primary end point of safety; the rate of treatment-emergent serious adverse events within 4 weeks of any infusion was similar in all four groups: group 1, 0% (95% CI 0-26.5%); group 2, 7.7% (95% CI 0.2-36%); group 3, 7.7% (95% CI 0.2-36%) and group 4, 9.1% (95% CI 0.2-41.3%). Additionally, there were no reported infusion-related reactions, hypersensitivities or amyloid-related imaging abnormalities. Laromestrocel improved clinical assessments at 39 weeks compared to placebo, as measured by a composite AD score (secondary end point was met: group 2 versus placebo change: 0.38; 95% CI -0.06-0.82), Montreal cognitive assessment and the Alzheimer's Disease Cooperative Study Activities of Daily Living. At 39 weeks, Laromestrocel slowed the decline of whole brain volume compared to placebo (n = 10) by 48.4% for all treatment groups combined (groups 2-4: P = 0.005; n = 32) and left hippocampal volume by 61.9% (groups 2-4, P = 0.021; n = 32), and reduced neuroinflammation as measured by diffusion tensor imaging. The change in bilateral hippocampal atrophy correlated with the change in mini-mental state exam scores (R = 0.41, P = 0.0075) in all study patients (N = 42). Collectively these results support safety of single and multiple doses of laromestrocel treatment for mild AD and provide indications of efficacy in combating decline of brain volume and potentially cognitive function. Larger-scale clinical trials of laromestrocel in AD are warranted. ClinicalTrials.gov registration: NCT05233774 .

Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.

The long-term effects and outcomes of human mesenchymal stem cell (MSC) therapy in patients with severe coronavirus disease 2019 (COVID-19) remain poorly understood. This study aimed to evaluate the extended safety and efficacy of MSC treatment in severe patients with COVID-19 who participated in our earlier randomized, double-blind, placebo-controlled clinical trial, with follow-up conducted over 3 years.

Despite the routine clinical use of extracorporeal photopheresis (ECP) for the last decades, there has been no sufficient investigation on the intra-apheresis dynamics of mononuclear cells (MNCs).

We conducted a multicenter, open-label, randomized phase 2 study to assess the efficacy of nivolumab (Nivo) as maintenance therapy for patients with acute myeloid leukemia (AML) in first complete remission (CR) or CR with incomplete hematologic recovery who were not candidates for stem cell transplant. Patients were stratified and randomized to observation (Obs) or Nivo (3 mg/kg IV every 2 weeks for 46 doses). The primary end point was progression-free survival (PFS) defined as time to disease relapse or death due to any reason. Secondary end points included overall survival (OS), and evaluation of adverse events (AEs) after Nivo administration. Eighty patients were enrolled with median duration of follow-up of 24 months (33 months among survivors). PFS was 13.2 months in the Nivo arm and 10.9 months in the Obs arm. Overall PFS curves were not statistically significantly different. The median OS was 53.9 months in the Nivo arm and 30.9 months in the Obs arm. There were more AEs of any type (regardless of attribution) on the Nivo arm; 27 patients (71%) on the Nivo arm had a grade ≥3 AE compared with 5 patients (12%) on the Obs arm (P < .001). Nivo maintenance after AML chemotherapy failed to improve the PFS and OS in this randomized phase 2 study. There were increased AEs and serious AEs (SAEs) with Nivo, but these AEs and SAEs were expected and manageable. This trial was registered at www.ClinicalTrials.gov as #NCT02275533.

Retrospective studies suggested that haploidentical transplantation combined with unrelated cord blood might improve survival for patients with haematological malignancies. We aimed to assess whether transplantation of haploidentical peripheral blood stem cells (PBSCs) plus unrelated cord blood would achieve superior disease-free survival compared with transplantation of haploidentical PBSCs plus bone marrow in this population.

Remote ischemic conditioning (RIC) is a simple and low-cost intervention that is thought to increase collateral blood flow through the vasodilatory effects of nitric oxide (NO) produced by the endothelium and red blood cells (RBCs). This study aims to investigate whether RIC affects RBC deformability and levels of NO and nitrite in patients with ischemic stroke.

To assess the impact of a single intra-articular (IA) injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with knee osteoarthritis (OA), a randomized, double-blind, placebo-controlled study was conducted. The study included 24 patients with knee OA who were randomly assigned to receive either a single IA injection of BM-MSCs or normal saline. Changes in the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Injury and Osteoarthritis Outcome Score (KOOS) after IA injection were assessed at 3, 6, 9, and 12 months. Magnetic resonance imaging (MRI) with T2 mapping sequences was conducted for knee cartilage assessment at baseline and at 3 and 12 months. The MSC group showed between-group improvement in WOMAC (-5.0 ± 3.6 vs. -0.1 ± 5.5, P = 0.02) and KOOS (23.9 ± 18.3 vs. 7.2 ± 15.9, P = 0.028) scores at 9 months compared with the control group. The MSC group exhibited a less sharp increase in the mean T2 value of the medial compartment than the control group at 12 months, with no serious adverse events observed during follow-up. A single IA injection of allogeneic BM-MSCs provided satisfactory pain relief for patients with knee OA compared with the control group at 9 months. Quantitative T2 MRI mapping of the cartilage showed that IA BM-MSCs could have a preventive effect on OA progression for 12 months. Our findings suggest the potential of allogeneic BM-MSCs IA injection as a pain-relieving and disease-modifying treatment for patients with knee OA in the outpatient setting.

Neuropathic pain is a debilitating complication following spinal cord injury (SCI). Currently, effective treatments for SCI-induced neuropathic pain are highly lacking. This clinical trial aimed to investigate the efficacy of combined intrathecal injection of Schwann cells (SCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in improving SCI-induced neuropathic pain. This study was a parallel-group, randomized, open-label, active-controlled phase II trial with two arms, including treatment and control groups. Patients with complete SCI-induced neuropathic pain in the treatment group received a single combined intrathecal injection of BMSCs and SCs. Study outcome measures were International SCI Pain Basic Data Set (ISCIPBDS) and World Health Organization (WHO) Quality of Life Assessment Instrument (WHOQOL-BREF). A total of 37 (55.2%) and 30 (44.8%) patients in the treatment and control groups were followed up for 6 months, respectively. Significant reductions in mean scores of interference items in the treatment group, including daily activities (P < 0.001), mood (P < 0.001), and sleep (P < 0.001), were found at 6 months after the injection compared with the control one. Similarly, pain frequency (P = 0.002), mean (P = 0.001), and worst (P = 0.001) numeric rating scale (NRS) pain intensity scores showed significant reductions in the treatment group after 6 months compared with the control one. Based on multiple regression analysis controlled for potential confounders, significant associations between changes in all outcome measures over the study period and the treatment group were found. This clinical trial indicated the efficacy of combined cell therapy in improving the neuropathic pain and quality of life in complete SCI patients. Future investigations should evaluate the effects of combination of this strategy with other existing therapies for SCI-induced neuropathic pain. This clinical trial was also registered prospectively at the Iranian Registry of Clinical Trials (IRCT20200502047277N8).

Effects of Dapagliflozin (Dapa) and Dapagliflozin-Saxagliptin combination (Combo) was examined on peripheral blood derived CD34 + Hematopoetic Stem Cells (HSCs) as a cellular CVD biomarker. Both Dapa (a sodium-glucose co-transporter 2 or SGLT2, receptor inhibitor) and Saxagliptin (a Di-peptydl-peptidase-4 or DPP4 enzyme inhibitor) are commonly used type 2 diabetes mellitus or T2DM medications, however the benefit of using the combination has not been evaluated for cardio-renal risk assessment, in a real-life practice setting, compared to a placebo.