Stem Cells , Tissue Engineering and Hematopoietic Elements Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal Modeling the Neurovascular Niche

Premature infants have chronic hypoxia, resulting in cognitive and motor neurodevelopmental handicaps caused by suboptimal neural stem cell (NSC) repair/ recovery in neurogenic zones (including the subventricular and the subgranular zones). Understanding the variable central nervous system repair response is crucial to identifying “at risk” infants and to increasing survival and clinical improvement of affected infants. Using mouse strains found to span the range of responsiveness to chronic hypoxia, we correlated differential NSC survival and self-renewal with differences in behavior. We found that C57BL/6 (C57) pups displayed increased hyperactivity after hypoxic insult; CD-1 NSCs exhibited increased hypoxia-induced factor 1 (HIF-1 ) mRNA and protein, increased HIF1 , and decreased prolyl hydroxylase domain 2 in nuclear fractions, which denotes increased transcription/translation and decreased degradation of HIF-1 . C57 NSCs exhibited blunted stromal-derived factor 1-induced migratory responsiveness, decreased matrix metalloproteinase-9 activity, and increased neuronal differentiation. Adult C57 mice exposed to hypoxia from P3 to P11 exhibited learning impairment and increased anxiety. These findings support the concept that behavioral differences between C57 and CD-1 mice are a consequence of differential responsiveness to hypoxic insult, leading to differences in HIF-1 signaling and resulting in lower NSC proliferative/migratory and higher apoptosis rates in C57 mice. Information gained from these studies will aid in design and effective use of preventive therapies in the very low birth weight infant population. (Am J Pathol 2009, 175:2133–2145; DOI: 10.2353/ajpath.2009.090354) Preterm birth is known to result in cognitive and motor disabilities and recent evidence suggests that there can be significant recovery over time in some patients. More than 1% of all live infants in the United States weigh less than 1000 g, and the survival rate for this population ranges from 60 to 85%. The individuals that do survive exhibit a high rate of neonatal morbidities and are frequently severely compromised. Many of these very low birth weight infants experience cerebral hypoxemia resulting from apnea and respiratory distress syndrome. Behavioral studies of this cohort have documented that approximately one quarter are functioning in the mentally retarded or borderline ranges at school age, 10% have cerebral palsy, and one half of these neonates need special assistance in school. The effects of hypoxia in the perinatal period include altered neuronal differentiation and synaptogenesis. The loss of neurons, glia, and their progenitor cells are thought to be the consequences of altered neuronal differentiation and synaptogenesis. Interestingly, significant improvement in academic functioning over time in this population has been reported. Although encouraging, this cognitive improvement is variable, and the repair/recovery mechanisms involved are not yet understood. The variable recovery observed in the very low birth weight infant population may be a result of the responsiveness of neurogenic zones (neurovascular niches) in the brain, namely the subventricular zone and the subgranular zone, due to a range of responsiveness to the chronic hypoxic insult of hypoxiainduced factor 1 (HIF1 ) induction and its downstream signaling cascades. Consistent with this notion, investigators, using a murine