Abstract
Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolated from the hemorrhagic cerebrospinal fluid obtained during therapeutic neuroendoscopic lavage in preterm infants with severe intraventricular hemorrhage. Our analyses demonstrate that these neural stem cells, although similar to human fetal cell lines, display distinctive hallmarks related to their regional and developmental origin in the germinal zone of the ventral forebrain, the ganglionic eminences that give rise to interneurons and oligodendrocytes. These cells can be expanded, cryopreserved, and differentiated in vitro and in vivo in the brain of nude mice and show no sign of tumoral transformation 6 months after transplantation. This novel class of neural stem cells poses no ethical concerns, as the fluid is usually discarded, and could be useful for the development of an autologous therapy for preterm infants, aiming to restore late neurogliogenesis and attenuate neurocognitive deficits. Furthermore, these cells represent a valuable tool for the study of the final stages of human brain development and germinal zone biology.
Highlights
Intraventricular hemorrhage (IVH) is a common complication of premature infants, occurring in 15% to 40% of preterm infants weighing less than 1500 g at birth and being common in extremely low birthweight neonates.[1,2,3] IVH is classified into four grades according to the extent of hemorrhage, development of subsequent ventricular dilatation, and parenchymal involvement: grade I—a hemorrhage restricted to subependymal region; grade II—a hemorrhage bleeding into de ventricles without dilation; grade III—an IVH with ventricular dilatation; and grade IV—an IVH with associated adjacent brain parenchyma infarction.[4]
To further confirm differentiation into glial lineages, we examined the expression of PDGFR, another oligodendrocyte marker, and S100β that was consistently coexpressed with glial fibrillary acidic protein (GFAP) in germinal zone (Gz)-neural stem cells (NSCs) differentiated in 2% B27 for 2 weeks (Figure S4)
We report here the isolation of a distinct class of NSCs, the Gz-NSCs, from hemorrhagic cerebrospinal fluid (CSF) samples of premature neonates diagnosed with IVH grade IV
Summary
Intraventricular hemorrhage (IVH) is a common complication of premature infants, occurring in 15% to 40% of preterm infants weighing less than 1500 g at birth and being common in extremely low birthweight neonates.[1,2,3] IVH is classified into four grades according to the extent of hemorrhage, development of subsequent ventricular dilatation, and parenchymal involvement: grade I—a hemorrhage restricted to subependymal region; grade II—a hemorrhage bleeding into de ventricles without dilation; grade III—an IVH with ventricular dilatation; and grade IV—an IVH with associated adjacent brain parenchyma infarction.[4] Some authors classify grade IV IVH separately because the presence of periventricular hemorrhagic infarction or other parenchymal lesions is generally not caused by extension of IVH into brain parenchyma and should be considered as a different pathological condition.[5] Around 10% to 15% of preterm infants develop severe (grade III-IV) IVH and those infants are at high risk to develop posthemorrhagic hydrocephalus, an expansion of the ventricles due to cerebrospinal fluid (CSF) accumulation (reviewed in Reference 6), and to present long-term neurological deficits with cognitive and motor disabilities.[6,7] IVH initiates in the periventricular germinal zone (Gz), known as germinal matrix, a highly proliferative, highly vascularized region around the lateral ventricles with a dense and fragile, endothelial-lined, vessel network.[8] From 24 to 32 weeks of gestation the Gz is most prominent in the caudo-thalamic groove, forming the ganglionic eminences of the ventricular zone (VZ), where late migrating cortical and thalamic neurons and oligodendrocyte precursors are born.[9] The ultimate cause of Gz bleeding remains unclear, but it is commonly accepted that it results from the combination of Gz vasculature vulnerability and blood pressure fluctuations associated with prematurity.[8] In the hemorrhage phase, there is a rupture of the Gz, occurring most often at the level of the medial ganglionic eminence, that entails loss of neural stem cells (NSCs) and disturbs the cytoarchitecture of the zone leading to abnormal neuronal, ependymal, and glio-genesis.[10,11] Current treatments for IVH are intended to decrease the intracranial pressure that can cause periventricular white matter compression and damage, impairment of brain development, and even death.[12,13] There is a standardized protocol neither for the type nor for the timing of the intervention,[14,15,16] but it has recently been shown that early removal of hemorrhagic CSF
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
