BACKGROUND: Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. Stem cell transplantation has evolved as a novel treatment modality in the management of TBI, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. Wharton\'s Jelly-derived mesenchymal stem cells (WJ-MSCs) have recently shown beneficial effects in the functional recovery of neurological deficits.
OBJECTIVE: To evaluate the safety and efficiency of MSC therapy in TBI.
METHODS: We present 6 patients, 4 male and 2 female aged between 21 and 27 years who suffered a TBI. These 6 patients underwent 6 doses of intrathecal, intramuscular (i.m.) and intravenous transplantation of WJ-MSCs at a target dose of 1 × 106/kg for each application route. Spasticity was assessed using the Modified Ashworth scale (MAS), motor function according to the Medical Research Council Muscle Strength Scale, quality of life was assessed by the Functional Independence Measure (FIM) scale and Karnofsky Performance Status scale.
RESULTS: Our patients showed only early, transient complications, such as subfebrile fever, mild headache, and muscle pain due to i.m. injection, which resolved within 24 h. During the one year follow-up, no other safety issues or adverse events were reported. These 6 patients showed improvements in their cognitive abilities, muscle spasticity, muscle strength, performance scores and fine motor skills when compared before and after the intervention. MAS values, which we used to assess spasticity, were observed to statistically significantly decrease for both left and right sides (P < 0.001). The FIM scale includes both motor scores (P < 0.05) and cognitive scores (P < 0.001) and showed a significant increase in pretest posttest analyses. The difference observed in the participants\' Karnofsky Performance Scale values pre and post the intervention was statistically significant (P < 0.001).
CONCLUSIONS: This study showed that cell transplantation has a safe, effective and promising future in the management of TBI.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton\'s jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects.
METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls.
RESULTS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment.
CONCLUSIONS: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies.
BACKGROUND: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

The effect of Wharton\'s jelly mesenchymal stem cells conditioned medium (WJMSCs-CM) and zinc oxide nanoparticles (ZnO-NPs) on cultured human gingival fibroblasts on various barrier membranes was investigated in this study. In this study, human gingival fibroblasts were prepared and cultured on three membranes: collagen membrane, acellular dermal matrix (ADM) with ZnO-NPs, and ADM without ZnO-NPs. WJMSCs-CM was given to the testing groups, while control groups received the same membranes without WJMSCs-CM. Following 48 and 72 h, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were performed to assess cell survival. Cell proliferation on the membranes was also evaluated using 4\',6-diamidino-2-phenylindole (DAPI) staining after 48 and 72 h. Field emission scanning electron microscopy was used to determine membrane surface structure and cell adhesion. Nanoparticles were also subjected to an energy-dispersive x-ray analysis to identify their chemical structure. Two-way analysis of variance was used to conduct the statistical analysis. The p-value ≤.05 was considered significant. When ADM-ZnO-NPs were combined with CM, fibroblast viability, and adhesion significantly differed from ADM-ZnO-NPs alone. DAPI results confirmed cell proliferation in all six groups on both experiment days. The abundance and concentrated distribution of cells during cell proliferation were found in CM-containing membranes, specifically the ADM-ZnO-NPs membrane, demonstrating the improved biocompatibility of the ADM-ZnO-NPs membrane for cell proliferation. The other groups did not significantly differ from one another. WJMSCs-CM positively affected the viability and proliferation of gingival fibroblasts, but only marginally. Under certain conditions, ZnO-NPs below a specific concentration increased the biocompatibility of the membranes.

Peripheral artery disease (PAD) affects more than 230 million people worldwide, with approximately 11% of patients presenting with advanced-stage PAD or critical limb ischemia (CLI). To avoid or delay amputation, particularly in no-option CLI patients with infeasible or ineffective revascularization, new treatment strategies such as regenerative therapies should be developed. Mesenchymal stem cells (MSCs) are the most popular cell source in regenerative therapies. They possess significant characteristics such as angiogenic, anti-inflammatory, and immunomodulatory activities, which encourage their application in different diseases. This phase I clinical trial reports the safety, feasibility, and probable efficacy of the intramuscular administration of allogeneic Wharton\'s jelly-derived MSCs (WJ-MSCs) in type 2 diabetes patients with CLI. Out of six screened patients with CLI, five patients were administered WJ-MSCs into the gastrocnemius, soleus, and the proximal part of the tibialis anterior muscles of the ischemic lower limb. The safety of WJ-MSCs injection was considered a primary outcome. Secondary endpoints included wound healing, the presence of pulse at the disease site, the absence of amputation, and improvement in visual analogue scale (VAS), pain-free walking time, and foot and ankle disability index (FADI). No patient experienced adverse events and foot or even toe amputation during the 6-month follow-up. Six months after the intervention, there were a significantly lower VAS score and significantly higher pain-free walking time and FADI score than the baseline, but no statistically significant difference was seen between other time points. In conclusion, allogeneic WJ-MSC transplantation in patients with CLI seems to be safe and effective.

The umbilical cord is a critical structure linking the fetus to the placenta and is surrounded by the amniotic fluid. It is composed of a vein, two arteries coiled around the vein, and Wharton\'s jelly surrounding the blood vessels. In this study, the stress distribution of the arteries, vein, and Wharton\'s jelly of an umbilical cord with extra-abdominal umbilical vein varix is analyzed for varying amniotic pressure using finite element analysis. Four diameters are considered for the umbilical vein, 6.5 mm, 11 mm, 15.5 mm, and 20 mm, with 6.5 mm corresponding to the normal vein diameter. The amniotic pressure is varied from 15-105 mmHg in steps of 15 mmHg, to simulate contractions during labour. Stress distribution is obtained and the peak stresses are analyzed. According to the results, the peak stress in the Wharton\'s jelly and the umbilical vein increases nonlinearly with increasing amniotic pressure. The peak stress in umbilical arteries initially decreases till the amniotic pressure reaches 45 mmHg and thereafter increases. This might be due to asymmetric deformation of the Wharton\'s jelly at the pressure range below arterial pressure.Clinical Relevance- This study could be useful in understanding the fundamental mechanics of extra-abdominal umbilical vein varix and help in development of better treatment protocols.

Stroke remains still the leading cause of long-term disability worldwide. Although interventions such as early reperfusion, intravenous thrombolysis, and endovascular revascularization have shown neurological benefit in stroke patients, there is still lack of effective treatment enabling regeneration of nervous tissue after cerebral ischemic episodes. Cell therapy is an evolving opportunity for stroke survivors with residual neurological deficits. The purpose of this study was to evaluate safety and potential efficacy of multiple administration of Hospital Exemption-Advanced Therapy Medicinal Product (HE-ATMP) comprising 3 × 107 Wharton\'s jelly mesenchymal stem cells (WJMSCs). A study group was composed of six patients-three women and three men. The patients were qualified to the treatment with diagnosis of chronic stroke (2-24 months after cerebral ischemic episode), during 2 years. All the patients undergone repeated rounds of HE-ATMP administration to the CSF (cerebrospinal fluid) via lumbar puncture. The control group consisted of six patients (two women and four men) who experienced stroke, treated at the same time (follow-up period: 24 months) using standard treatment methods, without endovascular treatment. To evaluate the results of the therapy, we used both impairment scales [National Institutes of Health Stroke Score (NIHSS)] and functional outcomes scales [Modified Rankin Scale (MRS) and Barthel Index (BI)]. In four patients, who received at least three repeated rounds of HE-ATMP, we reported neurological improvement and reduction of functional neurodeficiency. The biggest improvement concerned the reduction of speech disorders in two cases; significant improvement in the field of motor skills in three patients and reduction of apraxia and improvement of logical communication skills in two patients were also reported. All the patients became more independent. Significant improvement of the neurological condition using the same scales was registered only in two patients from the control group. We did not report any adverse events in the treated group during follow-up. At 1-year follow-up, we demonstrate safety and beneficial effect of WJMSC transplantation including neurological improvement and reduction of functional neurodeficiency. We are aware that the samples size of this study is relatively small. The treatment regimen needs to be further tested in larger group of patients.

The aim of the present study was to perform clinical, biochemical, and radiological evaluation of the efficacy of mesenchymal stem cells derived from Wharton jelly (WJ) present within the human umbilical cord in the treatment of knee osteoarthritis. Between 2018 and 2019, 10 patients with knee osteoarthritis for whom the conservative treatment was not beneficial were included in the study. Patients were clinically, radiologically, and biochemically evaluated before treatment initiation. Thereafter, the patients were intra-articularly injected using a solution containing 1 × 108 WJ-derived MSCs. Evaluations were performed on day 21 (V1) and 42 (V2) and month 3 (V3), 6 (V4), and 12 (V5) after the procedure. At 1-year post-injection, visual analogue scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Lequesne scores of patients were lower than those observed during the initial evaluation, whereas the mean 36-Item Short Form Health Survey score was higher. Cartilage thicknesses were found to be increased in all regions except in the medial femur, medial posterior femur, lateral posterior femur, and lateral posterior tibia regions in magnetic resonance imaging. A significant increase was observed in tumor necrosis factor-alpha, interleukin-1β, adiponectin, resistin, and interleukin-6 levels compared with pre-injection values. The leptin levels at 6-month and 1-year controls were lower than the pre-injection levels, and the decrease observed at 6 months was significant. In patients with knee osteoarthritis, intra-articular WJ-derived MSC injection causes significant pain reduction, satisfactory functional improvement, and increased patient satisfaction following a 1-year follow-up. These clinical improvements were supported by magnetic resonance images, along with changes in adiponectin and leptin levels in synovial fluid. Level of evidence: IV.

The aim of the present study was to explore the antileishmanial performance and wound healing effect of exosomes isolated from Wharton Jelly derived mesenchymal stem cells (WJ-MSCs) in combination with aloe-emodin. MSCs obtained from Wharton Jelly were characterized by flow cytometry. Exosomes were isolated from cultivated stem cells by ultacentrifugation method. Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), Nanoparticle Tracking Analysis (NTA) and flow cytometry were used for characterization of obtained exosomes. The cytotoxicities of characterized exosomes and aloe-emodin at different concentrations were investigated on L929 and J774 cell lines. Non-toxic concentrations of each agent were combined and their inhibitory efficacies on L.major promastigotes and amastigotes were investigated by different techniques such as MTT, parasite count and measurements of infection index. Finally, wound healing activities of combinations were examined on in vitro artifical wound model and compared with the use of exosomes alone. According to outcome of flow cytometic analysis, vesicles isolated from WJ-MSCs highly expressed the markers such as CD63 special for exosome profile. SEM and NTA results demonstrated that derived exosomes possessed dimensions between 150 to 200 nanometers and elicited the cup-shape specific to exosomes. Combinations including non-toxic dosages of exosomes and aloe-emodin demonstrated superior antileishmanial effectivenesses both on promastigotes and amastigotes in contrast to use of exosome alone since they lead to inhibition of promastigotes and amastigotes for 4 and 10-folds in comparison to control, respectively. Additionally, combinations elicited more rapidly and effective in vitro wound-healing performance in contrast to use of exosome alone. At the end of 24 h incubation application of combinations gave rise to wound closure at a rate of 72 %, while in the control group 52 % of wound area has not been healed, yet. These results reflect that mentioned combination has great potential to be used in treatment of cutaneus leishmaniasis (CL) since they have magnificient capacity to inhibit Leishmania parasites while enhancing wound healing.

Seeding cells are key factors in cell-based cartilage tissue regeneration. Monoculture of either chondrocyte or mesenchymal stem cells has several limitations. In recent years, co-culture strategies have provided potential solutions. In this study, directly co-cultured rat costal chondrocytes (CCs) and human Wharton\'s jelly mesenchymal stem (hWJMSCs) cells were evaluated as a candidate to regenerate articular cartilage.
Rat CCs are directly co-cultured with hWJMSCs in a pellet model at different ratios (3:1, 1:1, 1:3) for 21 days. The monoculture pellets were used as controls. RT-qPCR, biochemical assays, histological staining and evaluations were performed to analyze the chondrogenic differentiation of each group. The 1:1 ratio co-culture pellet group together with monoculture controls were implanted into the osteochondral defects made on the femoral grooves of the rats for 4, 8, 12 weeks. Then, macroscopic and histological evaluations were performed.
Compared to rat CCs pellet group, 3:1 and 1:1 ratio group demonstrated similar extracellular matrix production but less hypertrophy intendency. Immunochemistry staining found the consistent results. RT-PCR analysis indicated that chondrogenesis was promoted in co-cultured rat CCs, while expressions of hypertrophic genes were inhibited. However, hWJMSCs showed only slightly improved in chondrogenesis but not significantly different in hypertrophic expressions. In vivo experiments showed that all the pellets filled the defects but co-culture pellets demonstrated reduced hypertrophy, better surrounding cartilage integration and appropriate subchondral bone remodeling.
Co-culture of rat CCs and hWJMSCs demonstrated stable chondrogenic phenotype and decreased hypertrophic intendency in both vitro and vivo. These results suggest this co-culture combination as a promising candidate in articular cartilage regeneration.

Mesenchymal stem cells (MSCs) enhance tissue repair through paracrine effects following transplantation. The versican protein is one of the important factors contributing to this repair mechanism. Using MSC conditioned medium for cultivating monocytes may increase versican protein production and could be a good alternative for transplantation of MSCs. This study investigates the effect of culture medium conditioned by human MSCs on the expression of the versican gene in peripheral blood mononuclear cells (PBMCs) under hypoxia-mimetic and normoxic conditions.
The conditioned media used were derived from either adipose tissue or from Wharton’s jelly (WJ). Flow cytometry for surface markers (CD105, CD73, and CD90) was used to confirm MSCs. The PBMCs were isolated and cultured with the culture media of the MSC derived from either the adipose tissue or WJ. Desferrioxamine and cobalt chloride (200 and 300 µM final concentrations, respectively) were added to monocytes media to induce hypoxia-mimetic conditions. Western blotting was applied to detect HIF-1α protein and confirm hypoxia-mimetic conditions in PBMC. Versican gene expression was assessed in PBMC using RT-PCR. Western blotting showed that the expression of HIF-1α in PBMC increased significantly (p < 0.01).
RT-PCR results demonstrated that the expression of the versican and VEGF genes in PBMC increased significantly (p < 0.01) in hypoxia-mimetic conditions as compared to normoxia.
Based on the findings in the present study, the secreted factors of MSCs can be replaced by direct use of MSCs to improve damaged tissues.