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November 7, 2013

Disturbing the fetal brain during pregnancy impacts neural stem cell growth of offspring into adulthood

It is well known that there are events that happen in utero that can impact the child’s health as an adult. Changes in the maternal environment can have lasting effects for the child decades later. A new study led by The Hospital for Sick Children (SickKids) is the first to demonstrate how disturbances (like infections) during pregnancy can result in a surge of brain stem cells in offspring.  The study, published in the November 7 online edition of Cell Stem Cell, shows what occurs in the brain when the fetal environment is disturbed.

Using mouse models, the research team led by SickKids scientists Drs. Freda Miller and David Kaplan, explored the effect of a specific cytokine (or signalling molecule) on stem cell growth in the brain. When an individual gets an infection, the immune system fights back, in part, by secreting high levels of cytokines into circulation.  One of these cytokines, interleukin-6, is increased during an infection, and has been implicated in abnormal behavioral outcomes of maternal infections in mice.   

“We were surprised to learn that an acute increase in interleukin-6 that mimics a viral infection can actually have a huge impact on not only the number, but also the behaviour of adult stem cells in the brains of the adult offspring,” says Miller, Senior Scientist in Developmental & Stem Cell Biology at SickKids, and Professor in the Department of Molecular Genetics at the University of Toronto.

Stem cells build the brain during embryonic life, and during adulthood, regulate aspects of learning and memory and are thought to be involved in the repair of the injured brain. The body carefully controls the number and behaviour of stem cells to correctly build a well-functioning brain.

The study found that the increase in maternal interleukin-6 results in hyperactivation of a newly identified pathway that is important for stem cell development in the embryo. “We discovered that this pathway normally determines the precise number of stem cells in the brain needed for correct brain development, but because of the hyperactivity, the number of neural stem cells doubled,” says Miller.  

The mechanisms that regulate the development of stem cells that are found in adult tissues, are not well understood. This study offers new insight into how stem cell pools are formed in the brain, and supports the idea that the number of adult stem cells in the adult brain is determined in the embryonic brain. “We found that the brief surge of maternal interleukin-6 causes a surge in brain stem cell growth, so one of the next steps is to look into what impact this will have in the long run,” says Kaplan, Senior Scientist in Cell Biology at SickKids, and Professor in the Department of Molecular Genetics at the University of Toronto.

Earlier research in mice from the U.S. showed that the increase of interleukin-6 during viral infections in mouse mothers can lead to abnormal behaviour in their offspring. Additionally, maternal infections in humans have been associated with autism and schizophrenia.  

This previous work established that the offspring of the pregnant mice exhibited abnormal behaviour in adulthood, and the current study provides one potential cellular basis for this.  Together this work shows that the temporary disruption of a serious maternal infection may affect how the brain works into adulthood. “It’s as though the stem cells remember the initial shock they experienced in the embryo, and continue to be affected by it,” says Kaplan.

The findings of this study spark many new questions and present other avenues for future research. “One of our next steps is to explore the impact of a serious infection during pregnancy in combination with genetic factors. A mother’s infection during pregnancy may not seriously affect the unborn child if the child’s genetic makeup has no autism-risk genes, for example. However, for a baby who has autism-risk genes, the mother’s infection could be the environmental trigger that may lead to the disorder. This is something that we would like to work on in the future,” says Kaplan.

The research team would also like to study the consequences of the extra neural stem cells, since it is conceivable that having more stem cells helps repair the brain later in life, and what other environmental influences during pregnancy may cause perturbations in stem cell behaviour and brain development.  

The research was supported by Canadian Institutes of Health Research, the Three to Be Foundation, Brain Canada and SickKids Foundation.

About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally.  Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.

Media contacts:
Matet Nebres
The Hospital for Sick Children
matet.nebres@sickkids.ca
416-813-6380

Caitlin McNamee-Lamb
The Hospital for Sick Children
caitlin.mcnamee-lamb@sickkids.ca 416-813-7654 ext 201436