Background. Mesenchymal stem cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord-derived MSCs (UCMSCs) are particularly attractive as an off-the-shelf allogeneic treatment in emergency medical conditions. We aim to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methodology. Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents, and grandparents) were screened for genetic mutations, infections, cancers, and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 and followed up for 6 months. We measured cytokines using ELISA including anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1RA), interleukin 10 (IL-10), pro-/anti-inflammatory cytokine interleukin 6 (IL-6), and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Results. 11 healthy subjects (LD, n = 5 ; HD, n = 6 ; mean age of 55 ± 13 years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study especially in vital parameters and routine blood tests. At 6 months, the HD group had significantly higher levels of anti-inflammatory markers IL1-RA ( 705 ± 160 vs. 306 ± 36 pg / mL ; p = 0.02 ) and IL-10 ( 321 ± 27 vs. 251 ± 28 pg / m L; p = 0.02 ); and lower levels of proinflammatory marker TNF-α ( 74 ± 23 vs. 115 ± 15 pg / mL ; p = 0.04 ) compared to LD group. Conclusion. Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with a high-dose infusion.

Human umbilical cord–derived mesenchymal stem cells (hUC-MSCs) are a potential off-the-shelf product for acute ischemic stroke. This study explored the underlying mechanism of Cytopeutics® hUC-MSCs (Neuroncell-EX) as well as its feasibility and efficacy at two different doses: 2 × 10⁶ cells per rat and 4 × 10⁶ cells/rat in middle cerebral artery occlusion (MCAO) ischemic stroke model for 28 d. Modified neurological severity score (mNSS) and rotarod tests were evaluated at days 1, 4, 7, and 14. Transforming growth factor-beta 1 (TGF-β1), interleukin-1 receptor antagonist (IL-1Ra), and vascular endothelial growth factor (VEGF) were evaluated by enzyme-linked immunosorbent assay (ELISA) at days 4 and 28. Immunohistochemistry expression of aquaporin-4 (AQP4) and neuronal protein marker (NeuN) were performed at days 4 and 28, respectively. Both doses of Neuroncell-EX showed significant lower mNSS scores at days 7 and 14 compared to stroke control. Both Neuroncell-EX groups showed significant longer latency time at day 7, with only 4 × 10⁶ cells/rat group having significant longer time at day 14 than stroke control. At both time points, the 2 × 10⁶ cells/rat group had significantly higher TGF-β1 and IL-1Ra levels, with significantly increased TGF-β1 only observed in 4 × 10⁶ cells/rat group at day 4 compared to stroke control. The VEGF levels were significantly lower at day 4 but then significantly increased at day 28 in both Neuroncell-EX groups than stroke control. AQP4 expression was significantly higher in stroke control compared to healthy control at day 4. Both doses of Neuroncell-EX showed significantly higher NeuN expression compared to stroke control at day 28. There is a weak correlation between TGF-β1 with VEGF and inversely with AQP4. These results suggest that Neuroncell-EX is feasible and effective in promoting functional recovery and neuroprotection in ischemic rats, potentially through immunomodulation, angiogenesis, and neurogenesis mechanisms.

In the past decades, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have sparked interest in cellular therapy due to their immunomodulatory properties. Nevertheless, the fate of hUC-MSCs in the body remains poorly understood. This study aimed to investigate the biodistribution, homing and clearance of systemically administered hUC-MSCs in healthy BALB/c mice model. hUC-MSCs were labelled with GFP-Luc2 protein, followed by characterisation with flow cytometry. Upon intravenous infusion of transduced hUC-MSCs into the healthy BALB/c mice, the cells were dynamically monitored through the bioluminescent imaging (BLI) approach. Transduction of hUC-MSCs with GFP-Luc2 not only preserved the characteristics of MSCs, but also allowed live monitoring of transduced cells in the mice model. Upon systemic administration, BLI showed that transduced hUC-MSCs first localised predominantly in the lungs of healthy BALB/c mice and mainly remained in the lungs for up to 3 days before eventually cleared from the body. At terminal sacrifice, plasma chemistry biomarkers remained unchanged except for C-peptide levels, which were significantly reduced in the hUC-MSCs group. Histopathological findings further revealed that hUC-MSCs infusion did not cause any adverse effects and toxicity to lung, liver and heart tissues. Collectively, systemically administrated hUC-MSCs was safe and demonstrated dynamic homing capacity before eventually disappearing from the body.

Human umbilical cord-mesenchymal stem cells (hUC-MSCs) have been widely investigated as a new therapeutic agent to treat injuries and inflammatory-mediated and autoimmune diseases. Previous studies have reported on the safety of low-dose infusion of hUC-MSCs, but information on the cell behaviour at higher doses and frequency of injection of the cells remains uncertain. The aim of the present study was to demonstrate the safety and efficacy of hUC-MSCs by Cytopeutics® (Selangor, Malaysia) from low to an extremely high dose in different monitoring periods in healthy BALB/c mice as well as assessing the tumorigenicity of the cells in B-NDG SCID immunocompromised mice. Umbilical cord from two healthy human newborns was obtained and the isolation of the hUC-MSCs was performed based on previous established method. Assessment of the cells at different doses of single or multiple administrations was performed on healthy BALB/c mice in dose range finding, sub-acute (7 d and 28 d) and sub-chronic periods (90 d). Tumorigenicity potential of Cytopeutics® hUC-MSCs was also evaluated on B-NDG immunocompromised mice for 26 wk. Single or multiple administrations of Cytopeutics® hUC-MSCs up to 40 × 10⁶ cells per kilogramme of body weight (kg BW) were found to have no adverse effect in terms of clinical symptoms, haematology and other laboratory parameters, and histology examination in healthy BALB/c mice. hUC-MSCs were also found to reduce pro-inflammatory cytokines (IL-6 and TNF-α) in a dose-dependent manner. No sign of tumor formation was observed in B-NDG mice in the 26-wk tumorigenicity assessment. Single or multiple administration of allogenic Cytopeutics® hUC-MSCs was safe even at very high doses, is non-tumorigenic and did not cause adverse effects in mice throughout the evaluation periods. In addition, Cytopeutics® hUC-MSCs exhibited immunomodulatory effect in a dose-dependent manner.