Cell proliferation in human ganglionic eminence and suppression after prematurity-associated haemorrhage

In premature infants, germinal matrix haemorrhage in the brain is a common occurrence. However, cell proliferation and fate determination in the normal human germinal matrix is poorly understood. Human ganglionic eminence samples were collected prospectively from autopsies of premature and term infants with no evidence of pathological process (n=78; dying at post-menstrual age 14-88 weeks). The ganglionic eminence was thickest at 20-26 weeks and involuted by 34-36 weeks. Proliferating cells, detected by Ki67 immunoreactivity, were abundant throughout the ganglionic eminence prior to 18 weeks, after which a sharp boundary between the dorsal and ventral ganglionic eminence appeared with reduced cell proliferation in the dorsal region. Ki67 immunoreactivity persisted in the majority of ventral cells until ∼28 weeks, after which time the proportion of proliferating cells dropped quickly. The expression of cell lineage markers (such as Olig2, SOX2, platelet-derived growth factor receptor alpha) showed partitioning at the microscopic level. The hypothesis that germinal matrix haemorrhage suppresses cell proliferation was then addressed. In comparison to controls, germinal matrix haemorrhage (n=47; born at post-menstrual age 18-34 weeks followed by survival of 0 h to 98 days) was associated with significantly decreased cell proliferation if survival was >12 h. The cell cycle arrest transcription factor p53 was transiently increased and the oligodendroglial lineage markers Olig2 and platelet-derived growth factor receptor alpha were decreased. Cell death was negligible. A low level of microglial activation was detected. Haemorrhage-associated suppression of cell proliferation in premature human infants could partially explain the reduced brain size and clinical effects in children who suffer germinal matrix haemorrhage after premature birth.