Neural Stem Cells as Therapeutic Targets in Germinal Matrix Haemorrhage

Abstract

Haemorrhage within the germinal matrix with extension into the ventricle is commonly seen in very low birth weight babies. Outcome following severe haemorrhage, in particular when associated with post haemorrhagic hydrocephalus and congestive venous infarction is poor, whilst outcome following moderate degrees of haemorrhage remains variable. The Neural Stem Progenitor Cells (NSPC) within the GM have been shown to be exquisitely sensitive to micro-environmental cues, as such, haemorrhage within the GM is postulated to impact on neurological outcome through aberration of normal NSPC behaviour. Here we have developed a stereotactic model of autologous blood injection which recapitulates key features of Papile grade II/III Germinal Matrix Haemorrhage / Intraventricular Haemorrhage (GMH/IVH). This model demonstrates that GMH/IVH causes an activation of the NSPC within the wall of the lateral ventricle and increases the number of transient amplifying cells within the transcallosal pathway. Further to this RNA extraction from the NSPC (selected using a CD133 MACS protocol) revealed that GMH/IVH causes a significant down regulation of the transmembrane receptor Notch, a finding that was validated using Hes5 in situ hybridisation (ISH). Using a battery of behavioural tests including assessment of developmental landmarks, neuromotor and reflex development we found that GMH/IVH causes subtle but significant impacts on early neonatal development. GMH/IVH in transgenic mice overexpressing the polycomb group gene Bmi1 in NSC (Nestin+ve) revealed increased self-renewal and resistance to oxidative stress (properties of Bmi1 overexpression) reduced the impact of GMH on the oligodendrocyte population, it also revealed a unique behavioural phenotype.

We propose that GMH/IVH down regulates Notch in the NSPC causing a burst of precocious proliferation and depleting the NSPC pool, which impacts on neurological outcome due to altered cortical architecture. Further we suggest that modulation of NSPC properties may play role in determining outcome and should be further explored for its therapeutic potential.