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

Abstract

Chorioamnionitis is a major cause of preterm birth and brain injury. Bacterial invasion of the chorion and amnion, and/or the placenta, can lead to a fetal inflammatory response, which in turn has significant adverse consequences for the developing fetal brain. Accordingly, there is a strong causal link between chorioamnionitis, preterm brain injury and the pathogenesis of severe postnatal neurological deficits and cerebral palsy. Currently there are no treatments to protect or repair against brain injury in preterm infants born after pregnancy compromised by intrauterine infection. This review describes the injurious cascade of events in the preterm brain in response to a severe fetal inflammatory event. We will highlight specific periods of increased vulnerability, and the potential effects of therapeutic intervention with cell-based therapies. Many clinical trials are underway to investigate the efficacy of stem cells to treat patients with cerebral palsy. Stem cells, obtained from umbilical cord tissue and cord blood, normally discarded after birth, are emerging as a safe and potentially effective therapy. It is not yet known, however, which stem cell type(s) are the most efficacious for administration to preterm infants to treat brain injury-mediated inflammation. Individual stem cell populations found in cord blood and tissue, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), have a number of potential benefits that may specifically target preterm inflammatory-induced brain injury. MSCs have strong immunomodulatory potential, protecting against global and local neuroinflammatory cascades triggered during infection to the fetus. EPCs have angiogenic and vascular reparative qualities that make them ideal for neurovascular repair. A combined therapy using both MSCs and EPCs to target inflammation and promote angiogenesis for re-establishment of vital vessel networks is a treatment concept that warrants further investigation.

Autologous cord blood cell infusion in preterm neonates safely reduces respiratory support duration and potentially preterm complications

“…Preterm infants are vulnerable to brain injury, including HIE and IVH. HIE and IVH can lead to cerebral palsy (CP) causing functional impairments and lifelong disabilities . SPC in cord blood obtained several advantages over the use of other SPC source, including immunomodulatory capacity, anti‐fibrosis activity, anti‐apoptotic activity, endogenous repair, and growth promoting activity .…”

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.…”

“…Chorioamnionitis, fetal inflammation, and preterm birth are strongly associated with neuroinflammation and subsequent perinatal brain injury [8]. Neuroinflammation can be characterised by inflammatory cell infiltration into the brain and activation of resident microglia and astrocytes, which can then lead to cell death and impaired white matter development [9,10].…”

Chorioamnionitis, IL‐17A, and fetal origins of neurologic disease

“…For example, short treatment with IL-17A-neutralizing antibodies reduced brain injury after a HI by inhibiting neutrophil recruitment to affected sites 46 . Mesenchymal stem cells (MSC), sourced from cord blood and placental tissue, can suppress upregulation of cytokines IL-1α, IL-1β, IL-6, and TNF-α within the cerebral spinal fluid and periventricular brain region, resulting in attenuation of swelling and fluid formation around the brain 124, 125 . Together with endothelial progenitor cells (EPCs), MSCs may have the capacity to limit inflammation-based brain injury, while facilitating neuroreparative processes (such as vascular repair) to improve neurodevelopmental outcomes 125 .…”