The effects of Bone Morphogenetic Protein 4 on adult neural stem cell proliferation, differentiation and survival in an in vitro model of ischemic stroke

概要

[目的(Purpose)]
The subventricular zone (SVZ) of the lateral ventricles represents a main region where neural stem cells (NSCs) of the mature central nervous system (CNS) reside. The adult NSCs exhibit the potential to proliferate and differentiate into other neural cells, such as neurons and astrocytes. Bone morphogenetic proteins (BMPs) are the largest subclass of the transforming growth factor-(TGF-B) superfamily of ligands. BMP4 is a member of this family and plays important roles in CNS development and adult NSC differentiation. Furthermore, BMP4 expression levels are upregulated in CNS diseases as spinal cord injury and neonatal hypoxic-ischemia. However, the exact effects of BMP4 on SVZ adult NSCs in CNS ischemia are still unclear. I examined the behavior of adult NSCs under in vitro ischemic insults and explored the effects of BMP4 treatment on their responses.

[方法ならびに成績(Methods/Results)]
The SVZs of adult mice brains were isolated to obtain NSCs. Cultured NSCs were examined for their survival, proliferation and differentiation potential under normoxic (normal oxygen and glucose conditions) and ischemic conditions. Oxygen and glucose deprivation (OGD) were used as an in vitro model of ischemia. NSCs characteristics were further examined with BMP4 treatment in both normoxic and OGD conditions.

In contrast to normoxic and hypoxic conditions, I observed that anoxia resulted in reduced viability of adult NSCs, and that BMP4 treatment clearly rescued apoptotic cell death following anoxia.

Furthermore, BMP4 treatment exhibited a strong inhibitory effect on cellular proliferation of the adult NSCs in normoxic conditions. Moreover, such inhibitory effects of BMP4 treatment were also found in OGD conditions, despite the enhanced cellular proliferation of the adult NSCs that was observed under such ischemic conditions.

I further investigated adult NSCs differentiation response in similar conditions. Increased neuronal and astroglial commitment of adult NSCs were found in the OGD conditions, whereas a reduction in differentiated neurons and an increase in differentiated astrocytes were observed following BMP4 treatment.
Evaluation of Id genes family revealed changes in their expression levels under OGD conditions with and without BMP4 treatment.

[総括(Conclusion]
I examined the effects of oxygen and glucose deprivation (OGD) and/or BMP4 treatment on NSCs characteristics in vitro. The present study indicates that BMP4 modulates proliferation and differentiation of SVZ-derived adult NSCs and promotes cellular survival in the in vitro model of ischemic stroke.