Stem cells to regenerate the newborn brain

Abstract

Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that 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 corticospinal tract; a process which is only stimulated after a second injection with MSC. In search for the underlying mechanisms, we show that the administered MSC do not survive for long in the brain of the recipient, but do 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 respond to signals provided by the cerebral environment into which they are transplanted and adapt their growth and differentiation factor profile to the demands of the environment. We propose that communication between resident and transplanted stem cells regulates repair of the brain after injury. Finally, we show that MSC can enter the brain after nasal administration and that MSC accumulate at 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 treatment of newborn babies with brain injury within the near future.