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Delivery of In Vivo Acute Intermittent Hypoxia in Neonatal Rodents to Prime Subventricular Zone-derived Neural Progenitor Cell Cultures
Published on: November 2, 2015
Perinatal hypoxia/ischemia damages and depletes progenitors from the mouse subventricular zone
Christine Y Brazel1, Robert T Rosti, Sheri Boyce
1Stem Cell Biology Unit, Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, MD, USA.
Insights
Neonatal hypoxia-ischemia (H/I) damages the subventricular zone (SVZ) in 10-day-old mice, impacting neural stem and progenitor cells. This vulnerability contributes to long-term brain development issues.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Hypoxia-ischemia (H/I) is a significant cause of neurological disability in newborns.
- Previous studies identified vulnerability in rat subventricular zone (SVZ) progenitors post-H/I.
- Comparative studies in mice are needed to understand SVZ vulnerability in stroke models.
Purpose of the Study:
- To assess the relative vulnerability of the neonatal mouse SVZ to H/I.
- To characterize the cellular damage and cell death pathways in the mouse SVZ after H/I.
Main Methods:
- Unilateral common carotid artery cauterization followed by 70 min of H/I (10% O2) in 5-, 7-, and 10-day-old C57BL/6 mice.
- Hematoxylin and eosin staining to assess cellularity.
- Immunohistochemistry for caspase-3 and TUNEL staining to detect cell death.
Main Results:
- 10-day-old mice showed a 16% reduction in SVZ cellularity 18 hours post-H/I.
- Swollen cells and increased TUNEL+ and active-caspase-3+ cells were observed in the SVZ of 10-day-old mice.
- Dying cells were predominantly located in the mediolateral and lateral SVZ, not the neural stem cell region.
Conclusions:
- Neonatal mouse SVZ progenitors are vulnerable to hypoxic-ischemic insult.
- H/I-induced demise of early progenitors may deplete neuronal and oligodendrocyte progenitors.
- This progenitor loss contributes to cerebral dysgenesis and neurological deficits.
Abstract:
Hypoxia-ischemia (H/I) as a result of asphyxia at term remains a major cause of neurologic disability. Our previous studies in the P7 rat model of perinatal H/I have shown that progenitors within the subventricular zone (SVZ) are vulnerable to this insult. Since many investigators are using transgenic and knockout mice to determine the importance of specific molecules in the evolution of damage after a stroke, there is a need to perform comparative studies on the relative vulnerability of the mouse SVZ. Here we assess damage to the SVZ of 5-, 7- and 10-day-old C57BL/6 mice after unilateral common carotid artery cauterization followed by 70 min of H/I (10% O2). Whereas 5- and 7-day-old mice sustained little SVZ damage as assessed by hematoxylin and eosin staining, there was a 16% reduction of cellularity in 10-day-old animals by 18 h of recovery. Additionally, swollen cells were observed in the medial region of the SVZ of 10-day-old mice. However, few caspase-3+ and TUNEL+ cells were observed in this region, which contains the putative neural stem cells. Rather, the majority of the dying cells were situated in the mediolateral and lateral tail of the SVZ. At 18 h of recovery, there was a 2-fold increase in the frequency of TUNEL+ cells in the ipsilateral SVZ as well as a 3-fold increase in the frequency of active-caspase-3+ cells. We conclude that progenitors within the neonatal mouse SVZ are vulnerable to hypoxic/ischemic insult. The demise of these early progenitors likely leads to depletion of neuronal and late oligodendrocyte progenitors, contributing to cerebral dysgenesis.
