Urethral stricture and reconstruction are one of the thorny difficult problems in the field of urology. The continuous development of tissue engineering and biomaterials has given new therapeutic thinking to this problem. Bacterial cellulose (BC) is an excellent biomaterial due to its accessibility and strong plasticity. Moreover, adipose-derived stem cells (ADSCs) could enhance their wound healing ability through directional modification.
Aim: This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. Materials & methods: Safety and efficacy of haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 107, 2 × 107 and 5 × 107 cells, respectively), provided three injections and followed up for 96 weeks. Results & Conclusion: The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 107 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769).
Despite the various mechanisms that involved in the pathogenesis of Alzheimer's disease (AD), neuronal damage and synaptic dysfunction are the key events leading to cognition impairment. Therefore, neuroprotection and neurogenesis would provide essential alternatives to the rescue of AD cognitive function. Here we demonstrated that extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs-derived EVs, abbreviated as EVs) entered the brain quickly and efficiently following intranasal administration, and majorly accumulated in neurons within the central nervous system (CNS). Proteomics analysis showed that EVs contained multiple proteins possessing neuroprotective and neurogenesis activities, and neuronal RNA sequencing showed genes enrichment in neuroprotection and neurogenesis following the treatment with EVs. As a result, EVs exerted powerful neuroprotective effect on Aβ1–42 oligomer or glutamate-induced neuronal toxicity, effectively ameliorated neurologic damage in the whole brain areas, remarkably increased newborn neurons and powerfully rescued memory deficits in APP/PS1 transgenic mice. EVs also reduced Aβ deposition and decreased microglia activation although in a less extent. Collectively, here we provide direct evidence that ADSCs-derived EVs may potentially serve as an alternative for AD therapy through alleviating neuronal damage and promoting neurogenesis.
e14548 Background: Chimeric Antigen Receptor T cells (CAR-Ts) targeting CD19 have shown very promising clinical outcomes in treatment of B-cell linage hematological malignancies. However, many patients with relapsed diseases were found to have down-regulated/loss of CD19 surface expression after CD19 CAR-T therapy. To solve this issue of CD19 single-targeting escape, we explored the application of another B-cell antigen, CD20, for targeted CAR-T therapy. Methods: We constructed four CD20 targeting CARs (all with 4-1BB co-stimulatory signaling) base on single-chain variable fragments (scFV) derived from four well-studied CD20 specific antibodies: Leu16, Rituximab, Obinutuzumab, and Ofatumumab. Leu16, Rituximab, and Obinutuzumab belong to the type I anti-CD20 antibody family and appear to bind to different epitopes located on the large loop of CD20, whereas Ofatumumab is the type II anti-CD20 antibody which has been shown to interact with the hydrophobic residues on the small loop surrounding a deep binding cleft. Results: All four CAR-T cells can specifically recognized CD20 positive target cells in our pre-clinical studies. They all showed up-regulated antigen-specific cell activation and high level of IFN-g release upon CD20 stimulation, and CAR-T20-Ofatumumab cells appeared to have significantly higher cell activation and more than 2-fold increase in IFN-g release compared to the other three CAR-T20 cells with their scFVs deriving from type I anti-CD20 antibodies. CAR-T20-Ofatumumab cells also showed higher degranulation upon stimulation, and it displayed ~50% of increase in ability to kill CD20 positive cells in cytotoxicity assays. Conclusions: Our data suggested that CAR-T20-Ofatumumab has better in vitro function and appears to be a CAR superior to those derived from other three antibodies. A possible explanation for this observation is that Ofatumumab interacts with the hydrophobic residues on the small loop, which is very close to cell membrane and confers more extensive binding to the small loop with striking slow off-rate. Our results suggest that CAR-Ts targeting CD20 with the scFVs from the type II anti-CD20 antibody may have superior cell killing effects.
Human adipose-derived mesenchymal progenitor cells (haMPCs) are stem cells with multiple differentiation potential and immunomodulatory function. Re-Join® comprises in vitro expanded haMPCs from adipose tissue of patients combined with cell suspension solution. This study was undertaken to evaluate the efficacy and safety of Re-Join® in patients with symptomatic knee osteoarthritis (OA). Patients with Kellgren–Lawrence grade 1–3 knee OA were recruited from two centers and randomized to receive intra-articular injection of Re-Join® or HA. Pain and function were assessed by using WOMAC score, VAS, and SF-36. Magnetic resonance imaging (MRI) analysis was performed to measure cartilage repair. Adverse events (AEs) were collected. Fifty-three patients were randomized. Significant improvements in WOMAC, VAS, and SF-36 scores were observed in both groups at months 6 and 12 compared with baseline. Compared with the HA group, significantly more patients achieved 50% improvement of WOMAC and a trend of more patients achieved a 70% improvement rate in Re-Join® group after 12 months. Meanwhile, there was notably more increase in articular cartilage volume of both knees in the Re-Join® group than in the HA group after 12 months as measured by MRI. AEs were comparable between two groups. Most AEs were mild and moderate except one SAE of right knee joint infection in the HA group. Significant improvements in joint function, pain, quality of life, and cartilage regeneration were observed in Re-Join®-treated knee OA patients with good tolerance in a period of 12 months. ClinicalTrials.gov Identifier: NCT02162693 . Registered 13 June 2014.
Abstract Mesenchymal stromal cell‐derived extracellular vesicles (MSC‐EVs) turn out to be a promising source of cell‐free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose‐derived MSC‐EVs (haMSC‐EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC‐EVs in healthy volunteers. DiR‐labelled haMSC‐EVs were used to explore the distribution of nebulized haMSC‐EVs in the murine model. Pseudomonas aeruginosa ‐induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL‐6, TNF‐α and IL‐10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC‐EVs through the nebulized route. Twenty‐four healthy volunteers were involved and received the haMSC‐EVs once, ranging from 2 × 10 8 particles to 16 × 10 8 particles ( MEXVT study, NCT04313647 ). Nebulizing haMSC‐EVs improved survival rate to 80% at 96 h in P. aeruginosa ‐induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC‐EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC‐EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC‐EVs in lung injury diseases.
Existing clinical studies supported the potential efficacy of mesenchymal stromal cells as well as derived exosomes in the treatment of COVID-19. We aimed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from human adipose-derived MSCs (haMSC-Exos) in patients with COVID-19.The MEXCOVID trial is a phase 2a single-arm, open-labelled, interventional trial and patients were enrolled in Jinyintan Hospital, Wuhan, China. Eligible 7 patients were assigned to receive the daily dose of haMSCs-Exos (2.0 × 108 nano vesicles) for consecutively 5 days. The primary outcomes included the incidence of prespecified inhalation-associated events and serious adverse events. We also observed the demographic data, clinical characteristics, laboratory results including lymphocyte count, levels of D-dimer and IL-6 as well as chest imaging.Seven severe COVID-19 related pneumonia patients (4 males and 3 females) were enrolled and received nebulized haMSC-Exos. The median age was 57 year (interquartile range (IQR), 43 year to 70 year). The median time from onset of symptoms to hospital admission and administration of nebulized haMSC-Exos was 30 days (IQR, 15 days to 40 days) and 54 d (IQR, 34 d to 69 d), respectively. All COVID-19 patients tolerated the haMSC-Exos nebulization well, with no evidence of prespecified adverse events or clinical instability during the nebulization or during the immediate post-nebulization period. All patients presented a slight increase of serum lymphocyte counts (median as 1.61 × 109/L vs. 1.78 × 109/L). Different degrees of resolution of pulmonary lesions after aerosol inhalation of haMSC-Exos were observed among all patients, more obviously in 4 of 7 patients.Our trial shows that a consecutive 5 days inhalation dose of clinical grade haMSC-Exos up to a total amount of 2.0 × 109 nano vesicles was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested. This safety profile is seemingly followed by CT imaging improvement within 7 days. Further trials will have to confirm the long-term safety or efficacy in larger population.MEXCOVID, NCT04276987.
Amniotic membrane is a thin membrane on the inner side of the fetal placenta. Amniotic membrane has anti- inflammatory, anti-bacterial, anti-viral and immunological characteristics. Otherwise, the pluripotent properties and the regenerative ability of amniotic epithelial cells are an attractive source for tissue engineering. In addition, human amniotic epithelial cells have immunoregulation function and immunomodulatory properties, which are have cell therapeutic potential.
Abstract Background: We used textural analysis matrix to examine the spatial distribution of pixel values and detect the compositional variation of repair cartilage with treatment of allogeneic human adipose-derived mesenchymal progenitor cells (haMPCs). Methods: Eighteen patients were divided randomly into three groups with intra-articular injections of haMPCs: the low-dose (1.0×10 7 cells), mid-dose (2.0×10 7 ), and high-dose (5.0×10 7 ) group with six patients each. 3D texture analyses based on gray level run-length matrix (GLRLM) of the segmented ROIs on MRI relaxation time maps including T1rho, T2, T2 * and R2 * . Five GLRLM parameters were analyzed, including run length non-uniformity (RLNonUni), grey level non-uniformity (GLevNonU), long run emphasis (LngREmph), short run emphasis (ShrtREmp) and fraction of image in runs (Fraction). We used the difference before and after treatment (D values) as the object to avoid errors caused by individual differences. Two-tailed Pearson linear correlation analysis was used to investigate correlations between texture parameters and the WOMAC scores. Results: The heterogeneity of spatial distribution of MRI relaxation time mapping pixels from three groups was decreased to varying degrees at 48 weeks after intra-articular injection of haMPCs. Spatial distribution of cartilage relaxation time maps pixels were uneven and layered, especially in T2 maps. Compared with base time, there were significant differences among three dose groups in GLRLM features for T1rho map including RLNonUni, GLevNonU, LngREmph, for T2 map including LngREmph, GLevNonU, ShrtREmp, for T2 * map including RLNonUni, GLevNonU, and for R2 * map including RLNonUni, GLevNonU. WOMAC pain scores were associated with RLNonUni of T1rho map, GLevNonU of T2 map, LngREmph of T2 * map, LngREmph of R2 * map and Fraction of T1rho map, whereas no significant correlations in other measurements. Conclusions: MRI texture analysis of cartilage may allow detection of the compositional variation of repair cartilage with treatment of allogeneic haMPCs. This has potential applications in understanding mechanism of stem cells repairing cartilage and assessing response to treatment. Trial registration: Clinicaltrials, NCT02641860. Registered 3 December 2015.https://www.clinicaltrials.gov/ct2/show/NCT02641860
Abstract Background We used multimodal compositional magnetic resonance imaging (MRI) techniques, combined with clinical outcomes, to differentiate the alternations of composition in repair cartilage with allogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) in knee osteoarthritis (KOA) patients. Methods Eighteen patients participated a phase I/IIa clinical trial. All patients were divided randomly into three groups with intra-articular injections of haMPCs: the low-dose (1.0 × 10 7 cells), mid-dose (2.0 × 10 7 ), and high-dose (5.0 × 10 7 ) groups with six patients each. Compositional MRI examinations and clinical evaluations were performed at different time points. Results Significant differences were observed in quantitative T1rho, T2, T2star, R2star, and ADC measurements in patients of three dose groups, suggesting a possible compositional changes of cartilage with the treatment of allogeneic haMPCs. Also significant reduction in WOMAC and SF-36 scores showed the symptoms might be alleviated to some extent with this new treatment. As regards sensibilities of multi-parametric mappings to detect compositional or structural changes of cartilage, T1rho mapping was most sensitive to differentiate difference between three dose groups. Conclusions These results showed that multi-compositional MRI sequences might be an effective tool to evaluate the promotion of the repair of cartilage with allogeneic haMPCs by providing information of compositional alterations of cartilage. Trial registration Clinicaltrials, NCT02641860 . Registered 3 December 2015.
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