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The umbilical cord: A source of great richness

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Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have changed the course of lung injury and enabled the survival of infants born as early as 23-24 weeks of gestation, BPD still remains a common complication of extreme prematurity, and there is no specific treatment for it. Furthermore, children, adolescents, and adults who were born very preterm and developed BPD have an increased risk of persistent lung dysfunction, including early-onset emphysema. Therefore, it is possible that early-life pulmonary insults, such as extreme prematurity and BPD, may increase the risk of COPD later in life, especially if exposed to secondary challenges such as respiratory infections and/or smoking. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal and adult lung injuries. This paper summarizes the long-term pulmonary outcomes of preterm birth and BPD and discusses the recent advances of cell-based therapies for lung diseases, with a particular focus on BPD and COPD.
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Brain injury resulting from perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality in infants and chronic neurologic disability in surviving children. Recent multicenter clinical trials demonstrated the effectiveness of hypothermia initiated within the first 6 postnatal hours to reduce the risk of death or major neurological disabilities among neonates with HIE. However, in these trials, approximately 40% of cooled infants died or survived with significant impairments. Therefore, adjunct therapies are required to improve the outcome in neonates with HIE. Cord blood (CB) is a rich source of stem cells. Administration of human CB cells in animal models of HIE has generally resulted in improved outcomes and multiple mechanisms have been suggested including anti-inflammation, release of neurotrophic factors and stimulation of endogenous neurogenesis. Investigators at Duke are conducting studies of autologous CB infusion in neonates with HIE and in children with cerebral palsy. These pilot studies indicate no added risk from the regimens used, but results of ongoing placebo-controlled trials are needed to assess efficacy. Meanwhile, further investigations are warranted to determine the best strategies, that is, timing, dosing, route of delivery, choice of stem cells and ex vivo modulations, to attain long-term benefits of CB stem cell therapy.Bone Marrow Transplantation advance online publication, 10 September 2012; doi:10.1038/bmt.2012.169.
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Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury of the developing brain. Major brain lesions associated with CP are white matter damage (WMD) in preterm infants and cortico-subcortical lesions in term newborns. Cell therapy is considered promising for the repair of brain damage. Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a rich source of various stem cells that could be of interest in repairing perinatal brain damage. Our goal was to investigate the potential of hUCB-MNCs to prevent or repair brain lesions in an animal model of excitotoxic brain injury. We induced neonatal brain lesions using intracranial injections of ibotenate, a glutamate agonist, in 5-day-old rat pups. hUCB-MNCs were injected either intraperitoneally (i.p.) or intravenously (i.v.) soon or 24 h after ibotenate injection, and their neurological effects were assessed using histology and immunohistochemistry. hUCB-MNCs injected i.p. did not reach the systemic circulation but high amounts induced a significant systemic inflammatory response and increased the WMD induced by the excitotoxic insult. This effect was associated with a significant 40% increase in microglial activation around the white matter lesion. hUCB-MNCs injected i.v. soon or 24 h after the excitotoxic insult did not affect lesion size, microglial activation, astroglial cell density, or cell proliferation within the developing white matter or cortical plate at any concentration used. We demonstrated that hUCB-MNCs could not integrate into the developing brain or promote subsequent repair in most conditions tested. We found that the intraperitoneal injection of high amounts of hUCB-MNCs aggravated WMD and was associated with systemic inflammation.
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Delayed cord clamping (DCC) has been advocated during preterm delivery to improve hemodynamic stability during the early neonatal period. The hemodynamic effects of DCC in premature infants after birth have not been previously examined. Our objective was to compare the hemodynamic differences between premature infants randomized to either DCC or immediate cord clamping (ICC). This prospective study was conducted on a subset of infants who were enrolled in a randomized controlled trial to evaluate the effects of DCC versus ICC. Entry criteria included gestational ages of 24(0) to 31(6) weeks. Twins and infants of mothers with substance abuse were excluded. Serial Doppler studies were performed at 6 ± 2, 24 ± 4, 48 ± 6, and 108 ± 12 hours of life. Measurements included superior vena cava blood flow, right ventricle output, middle cerebral artery blood flow velocity (BFV), superior mesenteric artery BFV, left ventricle shortening fraction, and presence of a persistent ductus arteriosus. Twenty-five infants were enrolled in the DCC group and 26 in the ICC group. Gestational age, birth weight, and male gender were similar. Admission laboratory and clinical events were also similar. DCC resulted in significantly higher superior vena cava blood flow over the study period, as well as greater right ventricle output and right ventricular stroke volumes at 48 hours. No differences were noted in middle cerebral artery BFV, mean superior mesenteric artery BFV, shortening fraction, or the incidence of a persistent ductus arteriosus. DCC in premature infants is associated with potentially beneficial hemodynamic changes over the first days of life.
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Despite recent advances in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) using therapeutic hypothermia, at least 30% of the cooled infants will die or have moderate/severe neurological disability. Umbilical cord blood cells (UCBCs), which are readily available at birth, have been shown to reduce sensorimotor and/or cognitive impairments in several models of brain damage, representing a promising option for the treatment of neurological diseases. In this review, we discuss recent preclinical studies that assessed the effects of UCBC transplantation in the Rice-Vannucci animal model of HIE. We also review the possible cell types and mechanisms involved in the therapeutic effect of UCBC transplantation, including neuroprotection, immunomodulation, and stimulation of neural plasticity and regeneration. In addition, we discuss how neuroimaging methods, such as bioluminescence imaging, nuclear-medicine imaging, or magnetic resonance imaging, could be used to evaluate the biodistribution of UCBCs in both preclinical and clinical studies.
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The results from our previous trial revealed that infants with delayed cord clamping (DCC) had significantly lesser intraventricular hemorrhage (IVH) and late-onset sepsis (LOS) than infants with immediate cord clamping (ICC). A priori, we hypothesized that infants with DCC would have better motor function by 7 months corrected age. Infants between 24 and 31 weeks were randomized to ICC or DCC and follow-up evaluation was completed at 7 months corrected age. We found no differences in the Bayley Scales of Infant Development (BSID) scores between the DCC and ICC groups. However, a regression model of effects of DCC on motor scores controlling for gestational age, IVH, bronchopulmonary dysplasia, sepsis and male gender suggested higher motor scores of male infants with DCC. DCC at birth seems to be protective of very low birth weight male infants against motor disability at 7 months corrected age.
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The umbilical cord (UC) is a promising source of mesenchymal stromal cells (MSCs). UC-MSCs display very similar in vitro characteristics to bone marrow-MSCs and could represent a valuable alternative for cell-based therapies. However, it is still unclear whether UC-MSCs are prone or not to the acquisition of genomic imbalances during in vitro expansion. With the use of array-comparative genomic hybridization, we compared copy number variations of early (P2-P3) and late (>P5) passages of in vitro-expanded UC-MSCs. In two of 11 long-term UC-MSCs cultures, we observed the appearance of clones carrying genomic imbalances, which generated genetic mosaicism at intermediate passages. Although still able to reach the senescence phase, the cells carrying the genomic imbalance acquired a proliferative advantage, as demonstrated by the increase in frequency during long-term culture. Altogether, our results suggest that UC-MSC-based clinical protocols should be designed with caution; their clinical use should be preceded by array-comparative genomic hybridization screening for the acquisition of genomic imbalances during in vitro expansion.
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Background: Unrelated cord blood transplantation (UCBT) is associated with delayed hematopoietic recovery. Intrabone injection of cord blood cells (IB-UCBT) and double-UCBT (dUCBT) are designed to circumvent this problem. Methods: In a retrospective registry-based analysis, we compared outcomes of 87 IB-UCBT with 149 dUCBT recipients, after myeloablative conditioning regimen adjusting for the differences between the two groups. Median-infused total nucleated cells were 2.5×10/kg for IB-UCBT and 3.9×10/kg for dUCBT (P<0.001). Results: At day +30, cumulative incidence (CI) of neutrophil recovery was 76% and 62% (P=0.014) with a median time to engraftment of 23 and 28 days (P=0.001), after IB-UCBT and dUCBT, respectively. At day +180, CI of platelets recovery was 74% after IB-UCBT, and 64%, after dUCBT (P=0.003). In multivariate analysis, IB-UCBT was associated with neutrophil and platelets recovery and lower acute graft versus host disease (II-IV) (P<0.01). At 2 years, CI of nonrelapse mortality and relapse incidence were 30% and 25% after IB-UCBT and 34% and 29% after dUCBT, and disease-free survival was 45% and 37%, respectively. However, after landmark analysis at 4.7 months from transplantation, in multivariate analysis, relapse incidence was reduced (P=0.03), and there was a trend for better disease-free survival after IB-UCBT (P=0.09). Conclusion: Both approaches expand the possibility of offering UCBT to patients with hematopoietic malignancies; IB-UCBT is associated with faster myeloid and platelet recovery and lower acute graft versus host disease and may reduce the total cost. However, studies on cost effectiveness are needed to compare both strategies.
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Purpose of review: A brief delay in clamping the umbilical cord after birth offers health benefits to the newborn, with no adverse effects to the mother or her infant. Yet, in most obstetric practice, the cord is clamped soon after birth. A summary of the current evidence on delayed cord clamping and some reasons for the disconnect between the evidence and practice are discussed here, along with the recommendations from professional organizations and societies about this practice. Recent findings: In term infants, umbilical cord clamping between 30 and 180 s after birth results in higher concentrations of hemoglobin and hematocrit during the neonatal period, and increased serum ferritin levels and a lower incidence of iron-deficiency anemia at 4-6 months of age. These are important benefits for children in low and middle income countries where iron-deficiency anemia is highly prevalent. In preterm infants, delayed cord clamping for at least 30 s increases the concentrations of hemoglobin and hematocrit, improves mean systemic blood pressure, urine output, and cardiac function, and decreases the need for vasopressors and blood transfusions during the neonatal period. It also decreases the prevalence of necrotizing enterocolitis, sepsis, and intraventricular hemorrhage (all grades). Milking of the unclamped umbilical cord toward the infant soon after birth also has similar beneficial effects. In some studies, more infants in the delayed cord clamping groups required phototherapy for jaundice. Summary: Many professional organizations, societies, and experts recommend at least a 30-s delay before clamping the umbilical cord, especially after preterm births. The value of this practice for term births in resource-rich settings has not been evaluated.
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Background: Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods: Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results: Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions: Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage.
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This article provides a brief overview of pros and cons of clamping the cord too early (within seconds) after birth. It also highlights evolving data that suggest that delaying cord clamping for 30 to 60 seconds after birth is beneficial to the baby, with no measurable negative effects either the baby or the mother.
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Objective: We previously described a method for reducing early phlebotomy losses from very low birth weight (VLBW) neonates by obtaining the initial blood tests from otherwise discarded fetal blood from the placenta. In the present study we sought to; (1) measure the feasibility of performing this method in actual practice, (2) test the hypothesis that this method would result in higher hemoglobin concentrations and lower erythrocyte transfusion rates in the first week after birth. Methods: We conducted two studies in three Intermountain Healthcare NICUs. The first was a feasibility analysis involving 96 VLBW neonates, measuring the success of obtaining the NICU admission laboratory blood tests this way. The second study used case-control methodology to test the hypothesis that this method would result in a higher blood hemoglobin 12 to 24 h after birth, and a lower proportion receiving an erythrocyte transfusion in the first week. Result: In 91 of 96 VLBW neonates (95%) the initial blood tests were successfully obtained with this method. The success rate was not diminished by delayed cord clamping or cord milking, as it was successful in 35 of 36 (97%) such instances. Cases and controls were well matched on demographic and level of illness comparisons. Among cases the hemoglobin generally increased between birth and 12 to 24 h later, but among controls the hemoglobin generally decreased (P<0.05). In the week following birth fewer cases received vasopressors (P<0.01) and erythrocyte transfusions (P<0.001). Conclusion: We judge that it is feasible to collect the initial blood tests of VLBW neonates using otherwise discarded umbilical cord/placental blood, in that this can be accomplished in about 95% of VLBW deliveries. This method, which can be used in addition to either delayed clamping of the umbilical cord or cord milking, results in higher hemoglobin concentrations, less vasopressor use and fewer transfusions in the first week.
Article
Background: Optimal timing for clamping the umbilical cord at preterm birth is unclear. Early clamping allows for immediate transfer of the infant to the neonatologist. Delaying clamping allows blood flow between the placenta, the umbilical cord and the baby to continue. The blood which transfers to the baby between birth and cord clamping is called placental transfusion. Placental transfusion may improve circulating volume at birth, which may in turn improve outcome for preterm infants. Objectives: To assess the short- and long-term effects of early rather than delaying clamping or milking of the umbilical cord for infants born at less than 37 completed weeks' gestation, and their mothers. Search methods: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 May 2011). We updated this search on 26 June 2012 and added the results to the awaiting classification section. Selection criteria: Randomised controlled trials comparing early with delayed clamping of the umbilical cord and other strategies to influence placental transfusion for births before 37 completed weeks' gestation. Data collection and analysis: Three review authors assessed eligibility and trial quality. Main results: Fifteen studies (738 infants) were eligible for inclusion. Participants were between 24 and 36 weeks' gestation at birth. The maximum delay in cord clamping was 180 seconds. Delaying cord clamping was associated with fewer infants requiring transfusions for anaemia (seven trials, 392 infants; risk ratio (RR) 0.61, 95% confidence interval (CI) 0.46 to 0.81), less intraventricular haemorrhage (ultrasound diagnosis all grades) 10 trials, 539 infants (RR 0.59, 95% CI 0.41 to 0.85) and lower risk for necrotising enterocolitis (five trials, 241 infants, RR 0.62, 95% CI 0.43 to 0.90) compared with immediate clamping. However, the peak bilirubin concentration was higher for infants allocated to delayed cord clamping compared with immediate clamping (seven trials, 320 infants, mean difference 15.01 mmol/L, 95% CI 5.62 to 24.40). For most other outcomes (including the primary outcomes infant death, severe (grade three to four) intraventricular haemorrhage and periventricular leukomalacia) there were no clear differences identified between groups; but for many there was incomplete reporting and wide CIs. Outcome after discharge from hospital was reported for one small study; there were no significant differences between the groups in mean Bayley II scores at age seven months (corrected for gestation at birth (58 children)).No studies reported outcomes for the women. Authors' conclusions: Providing additional placental blood to the preterm baby by either delaying cord clamping for 30 to 120 seconds, rather than early clamping, seems to be associated with less need for transfusion, better circulatory stability, less intraventricular haemorrhage (all grades) and lower risk for necrotising enterocolitis. However, there were insufficient data for reliable conclusions about the comparative effects on any of the primary outcomes for this review.
Article
To compare two strategies to enhance placento-fetal blood transfusion in preterm neonates before 33 weeks of gestation. We recruited women at risk for singleton preterm deliveries. All delivered before 33 completed weeks of gestation. In this single-center trial, women were randomized to either standard treatment (clamping the cord for 30 seconds after delivery) or repeated (four times) milking of the cord toward the neonate. Exclusion criteria included inadequate time to obtain consent before delivery, known congenital abnormalities of the fetus, Rhesus sensitization, or fetal hydrops. Of 58 neonates included the trial, 31 were randomized to cord clamping and 27 were randomized to repeated milking of the cord. Mean birth weight was 1,263±428 g in the clamping group and 1,235±468 g in the milking group, with mean gestational age of 29.2±2.3 weeks and 29.5±2.7 weeks, respectively. Mean hemoglobin values for each group at 1 hour after birth were 17.3 g/L for clamping and 17.5 g/L for milking (P=.71). There was no significant difference in number of neonates undergoing transfusion (clamping group, 15; milking group, 17; P=.40) or the median number of transfusions within the first 42 days of life (median [range]: clamping group 0 [0-7]; milking group 0 [0-20]; P=.76). Milking the cord four times achieved a similar amount of placento-fetal blood transfusion compared with delaying clamping the cord for 30 seconds. National Research Register UK, www.nihr.ac.uk/Pages/default.aspx, N0051177741. I.
Article
A pilot study was conducted to determine the safety and feasibility of intravenous administration of autologous umbilical cord blood (CB) in young children with acquired neurologic disorders. Most CB units (CBUs) were electively stored in private CB banks. Unlike public banks, which utilize specific criteria and thresholds for banking, private banks generally store all collected CBUs. CBUs of eligible patients containing more than 1 × 10⁷ cells/kg were shipped to Duke from the banks of origin after confirming identity by HLA typing. On the day of infusion, CBUs were thawed and washed in dextran-albumin and infused intravenously. Patients were medicated with acetaminophen, diphenhydramine, and methylprednisolone before transfusion. Data regarding patients, infusions, and CBUs were collected retrospectively. Characteristics of CBUs were compared to existing data from CBUs publicly banked at the Carolinas Cord Blood Bank. From March 2004 to December 2009, 184 children received 198 CB infusions. Three patients had infusion reactions, all responsive to medical therapy and stopping the infusion. Median precryopreservation volume (60 mL vs. 89 mL, p < 0.0001), total nucleated cell count (4.7 × 10⁸ vs. 10.8 × 10⁸, p < 0.0001), and CD34 count (1.8 × 10⁶ vs. 3.0 × 10⁶, p < 0.0001) were significantly lower than publicly stored CBUs. Postthaw sterility cultures were positive in 7.6% of infused CBUs. IV infusion of autologous CB is safe and feasible in young children with neurologic injuries. Quality parameters of privately banked CBUs are inferior to those stored in public banks. If efficacy of autologous CB is established clinically, the quality of autologous units should be held to the same standards as those stored in public banks.
Article
The aim of the most recent studies on regenerative medicine was to focus on capability of stem cells deriving not only from haematopoietic system, but also from other organ and tissues, to regenerate damaged tissues. Stem cells derived from foetal annexes such as cord blood, placenta and amniotic fluid can be currently used in the effort to treat prenatally diagnosed genetic diseases. Cells derived from cord blood have been used since 1988 as an alternative source to realize stem cell transplantation. Compared with bone marrow, cord blood has shown the advantages of quick availability, less risk of GHVD, together with higher compatibility rates, and less risk of infections. Mesenchymal stem cells (MSCs) are multi-potent stem cells able to differentiate into different lineages, including osteocytes, chondrocytes, and adipocytes. Because of their trafficking capacity to injured tissues, clinical trials have been started evaluating the use of MSCs in the treatment of metabolic diseases like Hurler syndrome and metachromatic leukodystrophy, or Osteogenesis Imperfecta. MSCs were initially identified in adult bone marrow (BM-MSC), but cells resembling BM-MSCs have also been found in other tissues, both adult (peripheral blood, synovial membrane) and foetal (peripheral blood, liver, spleen, placenta, umbilical cord, and amniotic membrane). BM-MSCs have been widely used in clinical applications, as for cell-based therapy of Osteogenesis Imperfecta and metabolic diseases. In addition, human multi-potent MSCs present in second-trimester amniotic fluids may be a good target for prenatal gene therapy because of their expandability, their ability to differentiate into multiple lineages and their high transduction efficiency.
Article
We measured cell surface expression of CD34, HLA-DR, CD38, CD19, CD33, CD71, and CD45 antigens in the hematopoietic progenitor cells of fetal cord blood to investigate immunophenotypic changes at different gestational ages. These antigens were identified by flow cytometry in 11 fetuses (gestational age 19-24 wk, in 12 preterm (25-28 wk) and in ten newborn infants born at term. The frequency and number of CD34+ cells were higher in the blood of the 11 fetuses; in addition, a statistically significant inverse correlation between number of CD34+ cells and advancing gestational age was noted. The numbers of CD34+ CD19+, CD34+ CD33+, and CD34+ CD45+ coexpressing cells were significantly higher in the fetuses, whereas CD34+ CD38+ cells were more represented in the neonates at term. Gestational age was inversely correlated with the number of CD34+ CD19+ and CD34+ CD33+ coexpressing cells. A positive correlation between gestational age and CD34+ CD38+ cells was noted. The number of CD34- CD19+, CD34- CD38+, and CD34- CD45+ cells was higher in term infants; furthermore, a significant correlation between advancing gestational age and CD34- CD38+ or CD34- CD45+ cells was demonstrated. The proliferative capacity was also higher at lower gestational ages. These data suggest that the development and lineage commitment of fetal cord blood hematopoietic progenitor cells are very active during the last two trimesters of pregnancy. The most significant changes of hematopoietic cells maturation seem to occur within 25 wk of gestation.