A research group led by Kazunobu Sawamoto, a professor at Nagoya City University and National Institute for Physiological Sciences, and Koya Kawase, a pediatric doctor at Nagoya City University Hospital, has elucidated the significance of birth in the maintenance of neural stem cells (NSCs).
Birth is one of the most significant life events for animals. The transition from the intrauterine to the extrauterine environment causes various metabolic changes in individuals. Despite its significance, the role of birth in the developmental process remains incompletely understood. In the adult mammalian brain, NSCs are retained in the ventricular-subventricular zone(V-SVZ), where they continue to generate new neurons. The majority of postnatal NSCs are maintained in a quiescent state, enabling their long-term maintenance. In various tissues, metabolic profiles of the stem cell niche and of the stem cells themselves play a critical role in determining whether the cells remain quiescent or transition to an active, differentiated state. However, how birth-associated metabolic changes affect the fate of tissue stem cells, especially NSCs, is largely unknown.
Sawamoto's group focused on metabolic changes in radial glia (RG), the embryonic NSCs. The researchers performed metabolomics and single cell RNA-seq in the V-SVZ of full-term birth mice and preterm birth mice. They found that normal term birth triggers RG to become quiescent, which involves alteration of glutamine metabolism, resulting from increased expression of Glul, a gene encoding an enzyme that converts glutamate to glutamine. Importantly, they found that this cellular process is impaired by preterm birth.
"To understand the role of birth in the maintenance of quiescent NSCs, we evaluated the effects of preterm birth on postnatal neurogenesis," Sawamoto said.
Next, the team histologically analyzed the changes in the neurogenic activity of RG. They showed that RG transiently enter a neurogenic state via mTORC1 signaling in preterm birth mice. However, they also found that neurogenesis at the young-adult stage was decreased due to depletion of the NSC pool in preterm birth mice. Furthermore, they analyzed human autopsy brains and found that postnatal neurogenesis in the V-SVZ is decreased by preterm birth not only in mice but also in humans.
"Considering that postnatal neurogenesis plays an important role in brain development and plasticity in humans, the reduction in postnatal neurogenesis may be a cause of worse neurodevelopmental outcome in preterm infants," Kawase said.
Finally, to examine the role of birth-induced upregulation of Glul in RG, they generated Glul-knockdown and -overexpression lentiviruses and infected them to RG in vivo. Their experiments demonstrated that sufficient upregulation of Glul in RG at an appropriate time of birth is critical for the maintenance of quiescent NSCs.
"We have uncovered the significance of birth in the maintenance of quiescent NSCs. Considering that glutamine metabolism also regulates the functions of tissue stem cells other than NSCs, our findings enhance our understanding of the pivotal role of birth in tissue homeostasis and regenerative capacities," Sawamoto commented.
The full findings of the study are published in the Science Advances.
Article title: Significance of birth in the maintenance of quiescent neural stem cells. DOI:10.1126/sciadv.adn6377
In addition to Kazunobu Sawamoto and Koya Kawase, co-authors of this research article include researchers from Nagoya City University, National Institute for Physiological Sciences, Kindai University, University of Copenhagen, Children's National Hospital, and National Institute of Advanced Industrial Science and Technology.
