Matthew Covey, PhD, post doctoral fellow (right), with mentor Steve Levison, PhD, professor, Department of Neurology and Neurosciences, UMDNJ-New Jersey Medical School
resident neural stem cells after
perinatal brain injuries
L
|
ike the adult brain, the infant brain is vulnerable to disturbances in the flow of blood and oxygen. This condition, known as perinatal hypoxia/ischemia, is a complication of the birthing process that occurs with an incidence of between 1 and 2 per 1,000 live term births, with estimates that there are 14 million surviving children and young people in the U.S. alone. In addition, approximately 1.5% of all newborns in the U.S. are considered pre-term and up to 40% of these children are diagnosed with neurodevelopment handicaps. As many as 25% of these children are held back at least one school grade and more than half require special education. Ongoing health care costs are estimated at more than $3 billion per year, a figure nearly twice the current budget for the National Institute for Neurological Disorders and Stroke. The consequences and costs of developmental brain injuries are high and long lasting, but rarely is this patient population, or the causes of their disabilities, the subject of public discourse.
Our laboratory has previously shown that brain injury in the infant stimulates the proliferation of the stem cells within the “brain marrow,” resulting in a doubling in their number after just three days, and we have shown that these new precursors can generate new neurons and glia. Naturally, it would be detrimental to recovery from injury were any clinical interventions to interfere with the stimuli that coordinate the expansion of the neural stem cells and their attempts to repair the brain. Therefore, my studies have sought to understand the signals that stimulate their proliferation and the effects of commonly used anti-inflammatory drugs on the naturally occurring regenerative responses of the stem cells.
I have found that the levels of Leukemia Inhibitory Factor (LIF) and Interleukin-6 (IL-6) are significantly increased during the acute recovery interval after a perinatal hypoxic-ischemic insult. As LIF has been shown to participate in the homeostasis of embryonic stem cells, I evaluated the role of LIF in the self-renewal of SVZ stem cells. I found that adding LIF to the SVZ stem cells stimulated their growth. I also showed that LIF activates the Notch pathway, which is well known for its ability to prevent stem cells from differentiating towards neuronal or glial progenitors.
 |
Figure 1. Image depicts neurons (green), astrocytes (blue) and oligodendrocytes (red), the 3 major cell types of the brain, which were generated in vitro from rat adult neural stem cells. |
IL-6 is typically associated with inflammation, which occurs as a result of perinatal hypoxia/ischemia. Indomethacin is an anti-inflammatory drug that is commonly used in the clinic to prevent intraventricular hemorrhage and to treat babies with the congenital heart defect known as patent ductus arteriosus. A number of clinical studies have reported that Indomethacin decreases infant mortality and incidence of intraventricular hemorrhage, but the long-term consequences, and more specifically effects on motor, sensory and cognitive function, remain controversial.
Previously published work has shown that IL-6 decreases the number of stem cells formed in the hippocampus and that suppressing inflammation increases the numbers of these precursor cells. However, I have found that stem cells in the SVZ respond positively to IL-6. In fact, IL-6 is even more effective than LIF, and IL-6 is especially effective at maintaining the capacity of neural stem cells to self-renew over multiple passages. Surprisingly, these effects of IL-6 are blocked by Indomethacin. Furthermore, animals subjected to a hypoxic-ischemic injury and then treated with Indomethacin had fewer proliferating stem cells in SVZ than animals left untreated.
The results from our studies have important implications for the clinical management of infants who are born premature or who survive a perinatal hypoxic/ischemic insult. Based on our findings, it appears that strongly suppressing the inflammatory response negatively affects the neural stem cells. It seems that some inflammation is necessary to stimulate the neural stem cells of the SVZ in response to a brain injury. Without this expansion, the brain’s ability to heal itself may be severely compromised.
Matthew Covey earned a BSc (Hons) degree in neuroscience and a PhD in anatomy and structural biology from the University of Otago, Dunedin, New Zealand. He is currently a post doctoral fellow working in the laboratory of Steve Levison at UMDNJ-New Jersey Medical School.
