Could Cord Blood Cell Therapy Reduce Preterm Brain Injury?

Abstract

Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matter of the developing brain. Nearly 90% of preterm infants who later develop spastic CP have evidence of periventricular white matter injury. There are currently no treatments targeted at protecting the immature preterm brain. Umbilical cord blood (UCB) contains a diverse mix of stem and progenitor cells, and is a particularly promising source of cells for clinical applications, due to ethical and practical advantages over other potential therapeutic cell types. Recent studies have documented the potential benefits of UCB cells in reducing brain injury, particularly in rodent models of term neonatal hypoxia–ischemia. These studies indicate that UCB cells act via anti-inflammatory and immuno-modulatory effects, and release neurotrophic growth factors to support the damaged and surrounding brain tissue. The etiology of brain injury in preterm-born infants is less well understood than in term infants, but likely results from episodes of hypoperfusion, hypoxia–ischemia, and/or inflammation over a developmental period of white matter vulnerability. This review will explore current knowledge about the neuroprotective actions of UCB cells and their potential to ameliorate preterm brain injury through neonatal cell administration. We will also discuss the characteristics of UCB-derived from preterm and term infants for use in clinical applications.

Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb

“…; Li et al . ). Human UCB mononuclear cells have been investigated as a neuroprotective treatment in neonatal rats exposed to hypoxia–ischaemia (Meier et al .…”

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep

“…However, this preclinical animal study is the first to show that human UCB cells are protective for white matter development specifically in response to an inflammatory insult. Human UCB contains a heterogeneous mix of stem and progenitor cells which together, and separately, act in an immunomodulatory, angiogenic, anti-apoptotic and trophic manner for neuroprotective benefits [8,15,20]. The cell types present in UCB include mesenchymal stromal cells, haematopoietic stem cells, endothelial progenitor cells, T regulatory cells, and monocyte-derived suppressor cells [17], with each of these cell types potentially moderating the effects of different injurious cascades, both systemically and in the brain.…”

“…However, to date the majority of studies have used early intervention UCB therapy in experimental models of perinatal hypoxic-ischaemic brain injury at term [20], and therefore the mechanisms of injury, cell vulnerability, and regions of interest may be quite different to cerebral injury associated with intrauterine inflammation. Infants exposed to chorioamnionitis, and born preterm, have a high risk for neurodevelopmental impairment and long-term motor and behavioural deficits [6].…”

Perinatal Brain Injury As a Consequence of Preterm Birth and Intrauterine Inflammation: Designing Targeted Stem Cell Therapies

“…In the case of treating those vulnerable to preterm brain injury following chorioamnionitis, allogeneic cell treatment may be the most appropriate. Preterm babies are not the best candidates for autologous UCB transplants for a number of reasons; (i) collection volumes of UCB are proportional to gestational age and preterm birth is therefore implicated in low collection volumes (Wen et al, 2012; Mazzoccoli et al, 2016), (ii) it is unknown how maternal and fetal complications, including gestational diabetes, intrauterine growth restriction, preeclampsia, and chorioamnionitis, predominant in preterm births, alter the relative proportion of stem and immune cells (Wen et al, 2012; Li et al, 2014) and (iii) it has been suggested that, in large clinical trials, such as the Duke University UCB trial (clinicaltrails.gov), recruitment of participants was significantly lower than anticipated (63 recruited vs. a planned recruitment of 120) due to the lack of autologous cord blood storage in children that go on to be diagnosed with CP (Duke Translational Medicine Institute Website, 2012). …”