Impaired Cell Cycle Progression and Self-Renewal of Fetal Neural Stem and Progenitor Cells in a Murine Model of Intrauterine Growth Restriction

Abstract

Individuals with intrauterine growth restriction (IUGR) are at an increased risk for neurodevelopmental impairment. Fetal cortical neurogenesis is a time-sensitive process in which fetal neural stem cells (NSCs) follow a distinct pattern of layer-specific neuron generation to populate the cerebral cortex. Here, we used a murine maternal hypoxia-induced IUGR model to study the impact of IUGR on fetal NSC development. In this model, timed-pregnant mice were exposed to hypoxia during the active stage of neurogenesis, followed by fetal brain collection and analysis. In the IUGR fetal brains, we found a significant reduction in cerebral cortical thickness accompanied by decreases in layer-specific neurons. Using EdU labeling, we demonstrated that cell cycle progression of fetal NSCs was delayed, primarily observed in the G2/M phase during inward interkinetic nuclear migration. Following relief from maternal hypoxia exposure, the remaining fetal NSCs re-established their neurogenic ability and resumed production of layer-specific neurons. Surprisingly, the newly generated neurons matched their control counterparts in layer-specific marker expression, suggesting preservation of the fetal NSC temporal identity despite IUGR effects. As expected, the absolute number of neurons generated in the IUGR group remained lower compared to that in the control group due to a reduced fetal NSC pool size as a result of cell cycle defect. Transcriptome analysis identified genes related to energy expenditure and G2/M cell cycle progression being affected by maternal hypoxia-induced IUGR. Taken together, maternal hypoxia-induced IUGR is associated with a defect in cell cycle progression of fetal NSCs, and has a long-term impact on offspring cognitive development.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function

“…Unlike our data, however, they found significantly more early-born Ctip2 + /EdU + labeled neurons in cortical plate but fewer late-born Satb2 + /EdU + neurons in the intermediate zone or Brn2 + /EdU + neurons in the ventricular zone, suggesting a delayed transitioning of fetal NSCs from producing early-born to late-born neurons (Chou et al, 2022). They noted a delay in cell cycle progression, particularly in the G2/M phase during inward interkinetic nuclear migration, as responsible for the delayed transitioning of fetal NSCs from producing early-born to late-born neurons (Chou et al, 2022). This is different from our developing DG findings in which neuronal maturation occurred without any hindrance in IUGR and the neuronal populations remain more numerous than their sham counterparts throughout gestation.…”

“…They noted that a significantly lower number of Pax6 + /EdU + fetal NSCs in the IUGR group after 48 h of EdU incorporation, suggesting decreased self-renewal of fetal NSCs after IUGR (Chou et al, 2022) similar to our hippocampal findings. They also found a skew in cell fate decision with an accelerated transitioning from a stem to a progenitor state, resulting in a decrease in stem cell pool size (Chou et al, 2022). Unlike our data, however, they found significantly more early-born Ctip2 + /EdU + labeled neurons in cortical plate but fewer late-born Satb2 + /EdU + neurons in the intermediate zone or Brn2 + /EdU + neurons in the ventricular zone, suggesting a delayed transitioning of fetal NSCs from producing early-born to late-born neurons (Chou et al, 2022).…”

“…To our knowledge, this is the first description of IUGR-induced NSC depletion and premature neurogenesis in the developing hippocampal DG (Brown et al, 2021). A recent study examined the effects of IUGR on fetal cortical neurogenesis in a murine maternal hypoxia-induced IUGR model and found a significant reduction in the thickness of the cerebral cortical which is accounted for by decreases in layer-specific neurons at birth (Chou et al, 2022). They noted that a significantly lower number of Pax6 + /EdU + fetal NSCs in the IUGR group after 48 h of EdU incorporation, suggesting decreased self-renewal of fetal NSCs after IUGR (Chou et al, 2022) similar to our hippocampal findings.…”

“…They also found a skew in cell fate decision with an accelerated transitioning from a stem to a progenitor state, resulting in a decrease in stem cell pool size (Chou et al, 2022). Unlike our data, however, they found significantly more early-born Ctip2 + /EdU + labeled neurons in cortical plate but fewer late-born Satb2 + /EdU + neurons in the intermediate zone or Brn2 + /EdU + neurons in the ventricular zone, suggesting a delayed transitioning of fetal NSCs from producing early-born to late-born neurons (Chou et al, 2022). They noted a delay in cell cycle progression, particularly in the G2/M phase during inward interkinetic nuclear migration, as responsible for the delayed transitioning of fetal NSCs from producing early-born to late-born neurons (Chou et al, 2022).…”

“…A recent study examined the effects of IUGR on fetal cortical neurogenesis in a murine maternal hypoxia-induced IUGR model and found a significant reduction in the thickness of the cerebral cortical which is accounted for by decreases in layer-specific neurons at birth (Chou et al, 2022). They noted that a significantly lower number of Pax6 + /EdU + fetal NSCs in the IUGR group after 48 h of EdU incorporation, suggesting decreased self-renewal of fetal NSCs after IUGR (Chou et al, 2022) similar to our hippocampal findings. They also found a skew in cell fate decision with an accelerated transitioning from a stem to a progenitor state, resulting in a decrease in stem cell pool size (Chou et al, 2022).…”