Regeneration using endogenous neural stem cells following neonatal brain injury.

Despite recent advancements in perinatal care, the incidence of neonatal brain injury has not decreased. No therapies are currently available to repair injured brain tissues. In the postnatal brain, neural stem cells reside in the ventricular-subventricular zone (V-SVZ) and continuously generate new immature neurons (neuroblasts). After brain injury in rodents, V-SVZ-derived neuroblasts migrate toward the injured area using blood vessels as a scaffold. Notably, the neonatal V-SVZ has a remarkable neurogenic capacity. Furthermore, compared with the adult brain, after neonatal brain injury, larger numbers of neuroblasts migrate toward the lesion, raising the possibility that the V-SVZ could be a source for endogenous neuronal regeneration after neonatal brain injury. We recently demonstrated that efficient migration of V-SVZ-derived neuroblasts toward a lesion is supported by neonatal radial glia via neural cadherin (N-cadherin)-mediated neuron-fiber contact, which promotes RhoA activity. Moreover, providing blood vessel- and radial glia-mimetic scaffolds for migrating neuroblasts promotes neuronal migration and improves functional gait behaviors after neonatal brain injury. In the V-SVZ, oligodendrocyte progenitor cells (OPCs) are also generated and migrate toward the surrounding white matter, where they differentiate and form myelin. After white matter injury in rodents, the production and subsequent migration of V-SVZ-derived OPCs are enhanced. In the neonatal period, administration of growth factors at a specific time promotes oligodendrocyte regeneration and functional recovery after brain injury. These findings suggest that activating the high regenerative capacity that is specific to the neonatal period could lead to the development of new therapeutic strategies for neonatal brain injury.

Adult neurogenesis and its role in brain injury and psychiatric diseases.

In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self-renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramón y Cajal that 'once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably'. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of NSCs and oligodendrocyte precursor cells, another type of undifferentiated cell in the adult brain, in mood affective disorders.

Intrauterine Inflammation, Excessive Fetal Growth and Respiratory Morbidities in Moderate-To-Late Preterm Neonates.

INTRODUCTION: Respiratory morbidities in neonates are often progressive and life-threatening, and its early prediction is crucial. Intrauterine inflammation is one of the key control variables of respiratory morbidities in both very preterm and term neonates; however, little is known about its effects in the remaining group of moderate-to-late preterm neonates born between 32+0 and 36+6 weeks of gestation. This study aimed to confirm whether intrauterine inflammation is associated with respiratory morbidities in moderate-to-late preterm neonates. METHODS: A single-center retrospective observational study was conducted in neonates born between 32+0 and 34+6 weeks of gestation between April 2013 and March 2018. The correlation between respiratory morbidities (defined as a requirement for invasive mechanical ventilation longer than the median duration of 3 days) and intrauterine inflammation was assessed using multivariable logistic regression analysis. RESULTS: The study population comprised 242 neonates born at 33.7 ± 0.8 weeks of gestation and weighing 1,936 ± 381 g. The multivariable model to predict the outcome comprised respiratory distress syndrome (odds ratio [OR]: 9.1; 95% confidence interval [CI]: 3.7-22.5; p < 0.001), lower gestational age (per week; OR: 0.5; 95% CI: 0.3-0.8; p < 0.005), higher birth-weight z-score (OR: 1.6; 95% CI: 1.2-2.2; p < 0.005), lower cord blood pH (per 0.10; OR: 0.5; 95% CI: 0.3-0.7; p < 0.005), and chorioamnionitis (OR: 2.8; 95% CI: 1.1-7.2; p < 0.05). CONCLUSION: Together with the incidence of respiratory distress syndrome and gestational age, chorioamnionitis and high birth-weight z-scores were associated with an increased incidence of respiratory morbidities in moderate-to-late preterm neonates. The deleterious impact of intrauterine inflammation on the lungs may be common in neonates of virtually all gestational ages. Traditional admission policy of neonatal intensive care units based on a threshold birth-weight, may leave a group of neonates without close observation despite their increased risks for respiratory morbidities.

Neonatal MRI in preterm infants with periventricular leukomalacia and mild disability.

BACKGROUND: The aim of the present study was to describe the neonatal magnetic resonance imaging (MRI) findings of preterm infants with periventricular leukomalacia and mild neurological disability. METHODS: MRI findings at term equivalent were retrospectively investigated in eight preterm infants with mild disability and periventricular leukomalacia diagnosed on MRI in infancy. RESULTS: Linear, spotted, or macular areas of hyperintensity on T1-weighted imaging and hypointensity on T2-weighted imaging were identified in all subjects in the white matter lateral to the body of the lateral ventricle. No cystic lesions were seen. These findings were more widespread and more clearly visualized on T2-weighted imaging than T1-weighted imaging. CONCLUSIONS: Linear, spotted, or macular lesions that are hyperintense on T1-weighted imaging and hypointense on T2-weighted imaging are possibly compatible with periventricular leukomalacia.

Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury.

Radial glia (RG) are embryonic neural stem cells (NSCs) that produce neuroblasts and provide fibers that act as a scaffold for neuroblast migration during embryonic development. Although they normally disappear soon after birth, here we found that RG fibers can persist in injured neonatal mouse brains and act as a scaffold for postnatal ventricular-subventricular zone (V-SVZ)-derived neuroblasts that migrate to the lesion site. This injury-induced maintenance of RG fibers has a limited time window during post-natal development and promotes directional saltatory movement of neuroblasts via N-cadherin-mediated cell-cell contacts that promote RhoA activation. Transplanting an N-cadherin-containing scaffold into injured neonatal brains likewise promotes migration and maturation of V-SVZ-derived neuroblasts, leading to functional improvements in impaired gait behaviors. Together these results suggest that RG fibers enable postnatal V-SVZ-derived neuroblasts to migrate toward sites of injury, thereby enhancing neuronal regeneration and functional recovery from neonatal brain injuries.

Enhancement of neuroblast migration into the injured cerebral cortex using laminin-containing porous sponge.

After brain injury, neuroblasts generated from endogenous neural stem cells migrate toward the injured site using blood vessels as a scaffold, raising the possibility of reconstructing blood vessel network scaffolds as a strategy for promoting endogenous neuronal regeneration. In this study, we designed biomaterials based on the components and morphology of blood vessel scaffolds, and examined their ability to guide the migration of neuroblasts into a brain lesion site in mice. Transplanted porous sponge containing components of the basement membrane (BM) matrix enhanced neuroblast migration into the lesion, and detailed morphological examination suggested that the infiltrating cells used the BM sponge as a migration scaffold. Laminin (LN)-rich porous sponge also enhanced the migration of neuroblasts into the lesion, whereas BM gel and gelatin porous sponge did not. We conclude that the transplantation of LN-rich porous sponge promotes neuroblast migration into cortical lesions. This study highlights the possibility of using artificial blood vessel scaffolds to promote the regeneration of injured cerebral cortex.

Pontocerebellar hypoplasia type 3 with tetralogy of Fallot.

We report a male infant with pontocerebellar hypoplasia type 3 and tetralogy of Fallot. He showed optic nerve atrophy, progressive microcephaly, severe psychomotor developmental delay, and vesicoureteral reflux. Magnetic resonance imaging revealed severe hypoplasia of the cerebellar vermis and hemisphere, and of the brainstem including the pons, and simplified gyral patterns in bilateral frontal lobes. An unknown etiology differing from other cases of PCH type 3 might have caused not only optic nerve atrophy and hypoplasia of the cerebellum and brainstem, but also cerebral and visceral malformations. To the best of our knowledge, this represents the first report of pontocerebellar hypoplasia with congenital cardiac malformation.

Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain.

Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and differentiate into mature neurons, suggesting that such new neurons may be able to replace neurons lost to degenerative disease or injury and improve or repair neurological deficits. Here, we tested whether delivering growth factors via gelatin hydrogel microspheres would support neurogenesis in the SVZ. Insulin-like growth factor-1 (IGF-1)-containing microspheres increased the number of new neurons in the SVZ. Hepatocyte growth factor (HGF)-containing microspheres increased the number of new neurons migrating from the SVZ towards the injured striatum in a stroke model in mouse. These results suggest that the strategy of using gelatin hydrogel microspheres to achieve the sustained release of growth factors holds promise for the clinical regeneration of damaged brain tissues from endogenous neural stem cells in the adult SVZ.