Neural Stem/Progenitor Cells Participate in the Regenerative Response to Perinatal Hypoxia/Ischemia

Abstract

Perinatal hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but ϳ50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions. We further show that production of new striatal neurons follows the expansion of NSPs. Increased proliferation within the NSP niche occurs at 2 d after perinatal H/I, and the proliferating cells express nestin. Of those stem-cell related genes that change, the membrane receptors Notch1, gp-130, and the epidermal growth factor receptor, as well as the downstream transcription factor Hes5, which stimulate NSP proliferation and regulate stem cellness are induced before NSP expansion. The mechanisms for the reactive expansion of the NSPs reported here reveal potential therapeutic targets that could be exploited to amplify this response, thus enabling endogenous precursors to restore a normal pattern of brain development after perinatal H/I.

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…78,79,83 Furthermore, an increase in BrdU þ cells was observed in the affected SVZ from 1 week to 3 weeks after HI, implying that cell proliferation is stimulated in this region. 14,[77][78][79]81,83,84 Interestingly, BrdU þ cells were also shown in the striatum 14,77,78,81,83 and cortical regions 14,77,82 from 1 to 4 weeks after the insult. This finding suggests that either proliferating cells in the SVZ migrate to these regions or that local progenitors proliferate because of molecular changes in the cell environment.…”

“…84 Notch1 was shown to be enriched in the SVZ and SGZ areas. 84,100 Interestingly, recent data show that ablation of Notch1 expression in GFAP-expressing stem cells in postnatal mice results in a substantial decrease in proliferating cells and an increased preference for neural cell fate in the SGZ. 100 Alternatively, overexpression of the intracellular portion of Notch1 (called NICD), which initiates transcription of target genes, [101][102][103] increases proliferation and maintains GFAP-expressing stem cells.…”

“…77,79,[81][82][83] These double-positive cells were clustered in chains in the striatum and cortex and displayed the morphology of migrating neuroblasts. [82][83][84] Studies investigating the differentiation rate of proliferating cells into neurons and their survival show contradicting results. Current data show a decrease, 14,78 increase, 83,84 or no change (cortical area) 14 in NeuN/BrdU double-labeled cells compared with healthy brains.…”

“…[82][83][84] Studies investigating the differentiation rate of proliferating cells into neurons and their survival show contradicting results. Current data show a decrease, 14,78 increase, 83,84 or no change (cortical area) 14 in NeuN/BrdU double-labeled cells compared with healthy brains. This discrepancy is possibly due to the use of different strains in the studies, which may affect the extent of brain damage after HI.…”

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

“…After the initial decrease, cell proliferation starts to increase and peaks at 72 h after HI (41). The proliferating cells after neonatal HI express markers of immature multipotent precursors, but not markers of lineage-restricted progenitor cells (56), leaving the possibility of replacing different types of lost cells. In the healthy adult brain, neurogenesis is necessary to maintain neurological function.…”