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Cindy van Velthoven

Friday 28 January 2011

Stem cells to regenerate the newborn brain

Promotor: Prof.dr C.J. Heijnen and prof.dr F.van Bel
Defence: 28 January 2011
Full text

Perinatal hypoxia-ischemia (HI) is defined as ‘a condition of impaired blood gas exchange leading, if it persists, to progressive hypoxemia and hypercapnia’ and may occur before, during or early after birth. The prevalence of perinatal HI in Western countries is approximately 2-6 per 1000 full-term births. HI-induced brain damage is associated with cognitive, motor and behavioral deficits later in life that can range from subtle to severe. Current therapeutic intervention strategies are limited, although mild hypothermia improves outcome when started within 6 hours after onset of ischemia. However, there is still need for effective interventions with an extended therapeutic time window.

The main focus of this thesis is to determine the potential of the use of mesenchymal stem cells to regenerate the neonatal brain after HI injury. The most important conclusions of this thesis are:
Transplantation of MSC after neonatal brain injury is an effective way to repair the damaged brain. One injection of MSC enhances proliferation, differentiation and results in decreased lesion volume and improved motor function. A second injection of MSC is more powerful in decreasing lesion volume and improving motor function. The effect of MSC treatment is also represented by remodeling of the CST; a process which is only stimulated after a second injection with MSC. The administered MSC do not survive very long in the brain of the recipient, but long enough to stimulate endogenous repair processes. Stimulation of repair by MSC is mediated via growth factors and is dependent on the bi-directional interplay between the administered MSC and the ischemic environment in the brain. MSC can sense the danger in the cerebral environment and will adapt their growth and differentiation factor profile to the demands of the environment. The communication between endogenous and exogenous stem cells has significant effects on the behavior of both transplanted and resident stem cells. The potential of meaningful repair of the brain after injury will depend on that communication. Manipulation of the expression profiles of growth and differentiation factors in the brain may be crucial for the repair of brain inury in the future. MSC are very potent in repairing brain injury in the neonatal brain. Probably the neonatal brain, which is still developing, has a greater potential to regenerate than the adult brain in view of greater plasticity of the young brain than that of the adult brain. The many processes that are active during development of the brain in the neonate, are also needed for repairing injury to the brain. In other words the neonatal brain is already in a repair-ready state; when injury ensues the reaction is almost instantaneously and more effective than in the adult brain.

MSC can enter the brain via the nasal route allowing migration of the MSC via the rostral migratory stream towards the site of injury. The combination of an easy to use administration route together with the extended therapeutic time window for MSC treatment and potent regeneration of lost brain tissue renders MSC treatment an excellent candidate for therapeutic use to treat neonates with brain injury within the near future.