Concept: Cord blood
Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a Phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 10(7) total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 10(7) /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017.
Seafood consumption during pregnancy is thought to be beneficial for child neuropsychological development, but to our knowledge no large cohort studies with high fatty fish consumption have analyzed the association by seafood subtype. We evaluated 1,892 and 1,589 mother-child pairs at the ages of 14 months and 5 years, respectively, in a population-based Spanish birth cohort established during 2004-2008. Bayley and McCarthy scales and the Childhood Asperger Syndrome Test were used to assess neuropsychological development. Results from multivariate linear regression models were adjusted for sociodemographic characteristics and further adjusted for umbilical cord blood mercury or long-chain polyunsaturated fatty acid concentrations. Overall, consumption of seafood above the recommended limit of 340 g/week was associated with 10-g/week increments in neuropsychological scores. By subtype, in addition to lean fish, consumption of large fatty fish showed a positive association; offspring of persons within the highest quantile (>238 g/week) had an adjusted increase of 2.29 points in McCarthy general cognitive score (95% confidence interval: 0.42, 4.16). Similar findings were observed for the Childhood Asperger Syndrome Test. Beta coefficients diminished 15%-30% after adjustment for mercury or long-chain polyunsaturated fatty acid concentrations. Consumption of large fatty fish during pregnancy presents moderate child neuropsychological benefits, including improvements in cognitive functioning and some protection from autism-spectrum traits.
The aim of this exploratory study was to assess the safety and clinical effects of autologous umbilical cord blood (AUCB) infusion in children with idiopathic autism spectrum disorder (ASD). Twenty-nine children 2 to 6 years of age with a confirmed diagnosis of ASD participated in this randomized, blinded, placebo-controlled, crossover trial. Participants were randomized to receive AUCB or placebo, evaluated at baseline, 12, and 24 weeks, received the opposite infusion, then re-evaluated at the same time points. Evaluations included assessments of safety, Expressive One Word Picture Vocabulary Test, 4th edition, Receptive One Word Picture Vocabulary Test, 4th edition, Clinical Global Impression, Stanford-Binet Fluid Reasoning and Knowledge, and the Vineland Adaptive Behavior and Socialization Subscales. Generalized linear models were used to assess the effects of the response variables at the 12- and 24-week time periods under each condition (AUCB, placebo). There were no serious adverse events. There were trends toward improvement, particularly in socialization, but there were no statistically significant differences for any endpoints. The results of this study suggest that autologous umbilical cord infusions are safe for children with ASD. Tightly controlled trials are necessary to further progress the study of AUCB for autism. Stem Cells Translational Medicine 2018.
Despite advances in early diagnosis and behavioral therapies, more effective treatments for children with autism spectrum disorder (ASD) are needed. We hypothesized that umbilical cord blood-derived cell therapies may have potential in alleviating ASD symptoms by modulating inflammatory processes in the brain. Accordingly, we conducted a phase I, open-label trial to assess the safety and feasibility of a single intravenous infusion of autologous umbilical cord blood, as well as sensitivity to change in several ASD assessment tools, to determine suitable endpoints for future trials. Twenty-five children, median age 4.6 years (range 2.26-5.97), with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit, were enrolled. Children were evaluated with a battery of behavioral and functional tests immediately prior to cord blood infusion (baseline) and 6 and 12 months later. Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated. Significant improvements in children’s behavior were observed on parent-report measures of social communication skills and autism symptoms, clinician ratings of overall autism symptom severity and degree of improvement, standardized measures of expressive vocabulary, and objective eye-tracking measures of children’s attention to social stimuli, indicating that these measures may be useful endpoints in future studies. Behavioral improvements were observed during the first 6 months after infusion and were greater in children with higher baseline nonverbal intelligence quotients. These data will serve as the basis for future studies to determine the efficacy of umbilical cord blood infusions in children with ASD. Stem Cells Translational Medicine 2017.
Exposure to organochlorine pesticides was studied in a group of mother-infant pairs living in a rural area where agriculture is the main economic activity. Fumigation in this zone is performed with airplanes, thus affecting the inhabited areas around them, including schools. Heparinized venous blood of mothers and umbilical cords was used to evaluate the olive tail moment in the comet assay, and micronuclei, chromatin buds, and nucleoplasmic bridges in peripheral blood lymphocytes. Cord blood samples were taken at the moment of birth only from natural and normal parturitions. Determinations of hexachlorobenzene, aldrin, heptachlor epoxide, oxichlordane, t and c-chlordane, cis-nonachlor, mirex, alpha and beta-endosulfan, alpha, beta and gamma hexachlorocyclohexane, and p'p'-DDT, p'p'-DDE were conducted to establish the differential distribution of the toxicants between compartments, i.e., mother and umbilical cord. Significantly higher pesticide levels were found in umbilical cord plasma than in mothers' plasma for almost all compounds tested, except DDE and oxychlordane. Significantly higher olive tail moments were found in umbilical cords than in mothers, whereas micronuclei frequencies were higher in mothers than in umbilical cords. However, neither the levels of micronuclei nor the olive tail moment were correlated with pesticide levels. Given that no other exposure to toxic compounds has been identified in this region, the lack of correlation between genotoxicity biomarkers and pesticide levels may be due to the variability of the exposure and to endogenous processes related to lipid mobility during pregnancy, the metabolism of the compounds, and individual susceptibilities. © 2013 Wiley Periodicals, Inc.
Smoking is a major risk factor for atherosclerosis. In this study, we evaluated the effects of benzo[a]pyrene (BaP, a prominent component of tobacco smoke) on the function and pro-inflammatory response of human endothelial progenitor cells (EPCs). EPCs were isolated from umbilical cord blood and treated with different concentrations (10, 20 and 50 µmol/l) of BaP. The proliferation, migration, adhesion and angiogenesis of BaP-treated EPCs were evaluated using the cell counting kit-8 (CCK-8), Transwell assay, adhesion assay and in vitro tube formation assay, respectively. The activation of nuclear factor-κB (NF-κB) was evaluated by measuring the mRNA expression of NF-κB p65 and p50 by real-time RT-PCR and NF-κB translocation assay. Reactive oxygen species (ROS) production was determined by the reduction of fluorescent 2',7'-dichlorofluorescein diacetate (DCFH-DA). The results demonstrated that BaP treatment significantly inhibited the proliferation, migration, adhesion and angiogenesis of EPCs in vitro. In addition, BaP induced the release of interleukin (IL)-1β and tumor necrosis factor-α from these cells. Moreover, the exposure of EPCs to BaP induced ROS generation and the activation of NF-κB. Experiments with EPCs pre-treated with pyrrolidine dithiocarbamate, an inhibitor of NF-κB, revealed that the BaP-mediated inhibition of proliferation, migration, adhesion and angiogenesis of EPCs is mainly regulated by NF-κB. Thus, tobacco smoke may induce oxidant-mediated stress responses in EPCs and impair their function via the activation of the NF-κB pathway.
Recent advances in allogeneic hematopoietic cell transplant (allo-HCT) have led to an increasing use of alternative donors, including banked umbilical cord blood (UCB). Despite these advances, acute GVHD (aGVHD) and chronic GVHD (cGVHD) continue to be the leading causes of early and late transplant-related mortality. ABO-mismatch has been frequently reported as a risk factor for GVHD, however, data in the UCB recipients are limited. We hypothesized that as the lymphocytes in the cord blood are thought to be naive, they will therefore be less likely to mediate GVHD. Therefore, we analyzed the impact of ABO-mismatch on aGVHD and cGVHD in recipients of single and double UCB-HCT. In both univariate and multivariate analyses, presence of ABO-mismatch did not have an impact on aGVHD or cGVHD. Whereas ABO-compatible donors are preferred in recipients of URD-HCT, ABO compatibility generally need not be considered in recipients of UCB-HCT.Bone Marrow Transplantation advance online publication, 18 February 2013; doi:10.1038/bmt.2013.8.
Hematopoietic stem cells (HSCs) from umbilical cord blood have been successfully used to treat blood disorders but one major hurdle is the relatively low cell dose available. Double cord blood unit transplantation results in elevated engraftment failure because one unit predominates over the other. Various approaches are thus being undertaken to expand HSCs ex vivo from single cord blood units. We report here a protocol involving slow freezing (-1 °C per minute to -120 °C) + freezing medium containing DMSO + FBS + 24 h-50 % hWJSC-CM that enhances thaw-survival of CD34+ cells. Post-thawing, the fold, percentage and colony forming unit numbers of CD34+ cells were significantly increased (2.08 ± 0.3; 102 ± 1.17 %; 1.07 ± 0.02 respectively) while the percentages of apoptotic, necrotic, dead and sub-G1 phase cells (91.06 ± 3.63 %; 91.80 ± 5.01 %; 95.6 ± 3.61 %; 86.1 ± 16.26 % respectively) were significantly decreased compared to controls. Post-thaw culture in 24 h-50 % hWJSC-CM+FBS for 72 h showed further significant increases in CD34+ cells (fold: 2.28 ± 0.17; percentage: 153.3 ± 21.99 %, CFU: 1.6 ± 0.19) and significant decreases in apoptotic, necrotic, dead and sub-G1 cells (49.2 ± 3.59 %; 62.0 ± 4.30 %; 56.6 ± 5.06 %; 28.6 ± 5.74 % respectively) compared to controls. We hypothesize that these improvements are probably related to the high levels of cytokines, cell adhesion molecules and growth factors in hWJSC-CM that help to preserve cell membrane integrity during freezing and stimulate mitosis post-thaw. A 24 h-50 % hJWSC-CM may be a useful supplement for freezing CD34+ cells in cord blood banks.
Here, we describe the NeoThy humanized mouse model created using non-fetal human tissue sources, cryopreserved neonatal thymus and umbilical cord blood hematopoietic stem cells (HSCs). Conventional humanized mouse models are made by engrafting human fetal thymus and HSCs into immunocompromised mice. These mice harbor functional human T cells that have matured in the presence of human self-peptides and human leukocyte antigen molecules. Neonatal thymus tissue is more abundant and developmentally mature and allows for creation of up to ∼50-fold more mice per donor compared with fetal tissue models. The NeoThy has equivalent frequencies of engrafted human immune cells compared with fetal tissue humanized mice and exhibits T cell function in assays of ex vivo cell proliferation, interferon γ secretion, and in vivo graft infiltration. The NeoThy model may provide significant advantages for induced pluripotent stem cell immunogenicity studies, while bypassing the requirement for fetal tissue.
Twin neonates have a higher risk of respiratory complications, such as respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN), than singleton neonates. The purpose of this study was to evaluate the relationship between the cortisol levels in the umbilical cord and neonatal RDS/TTN in twin pregnancies.