Preterm birth is a major global health problem affecting 10% of live births with considerable mortality and morbidity. Perinatal white matter injury (WMI), diffuse or cystic, is the most common brain injury in premature infants.
Risk factors for the development of WMI include intrauterine infection as well as perinatal hypoxia-ischemia of the brain. Diffuse WMI is associated with permanent neurodevelopmental disabilities--including cognitive delay, motor deficits, and cerebral palsy.
Unfortunately, currently there is no therapy for diffuse WMI.
The brain consists of gray and white matter, which include the nerve cell bodies and the oligodendrocytes (OLs), respectively. OLs produce myelin that coats nerve cell fibers, enabling speedy transmission of impulses. Damage to OLs slows nerve transmission and impairs brain function.
During brain development, neural stem cells differentiate into oligodendrocyte precursors, which further differentiate into pre-oligodendrocytes (pre-OLs), which later mature into myelin-producing OLs. Pre-OLs predominate the white matter during the time of peak incidence of WMI (23-32 gestational weeks), and are the main population that is adversely affected in diffuse WMI. Hypoxia results in pre-OL death that is followed by generation of a new pool of pre-OLs. However, these new pre-OLs fail to mature into myelin-producing OLs. This maturation arrest leads to lack of myelin and impaired white matter (Figure 1).
A fundamental obstacle in understanding the mechanism of maturation arrest in the preterm brain and in developing novel therapies for diffuse WMI is the lack of an appropriate animal model. Here we proposed to use human embryonic stem cells (hESC)-derived OLs for modeling diffuse WMI.
Indeed, in preliminary results, we show the potential of hESC-derived OLs to model the hypoxia-induced maturation arrest. We will further use this model for screening and identifying molecules that will promote the maturation of arrested pre-OLs, which may serve as novel drugs for diffuse WMI (Figure 2).
In preliminary results we identified a small molecule that could overcome the maturation arrest.
The analysis of a potential therapeutic effect of candidate molecules in our cellular model cannot evaluate improvements in neurological functions such as motor capabilities. Therefore, it is essential to assess their effect in an in-vivo model.
A rodent animal model of chronic hypoxia exposure of newborn pups is widely used to mimic hypoxia-induced WMI of preterm human fetuses. In preliminary results, we show that treatment of hypoxia-exposed newborn mice with our identified small molecule, promoted a significant functional recovery and increased myelin production in the brain of the hypoxic mice.
The results of the project may pave the way for the development of novel therapies for diffuse WMI.
Figure 1: Progression of the oligodendroglial lineage through four major stages. The predominant cell population in cerebral white matter of the premature infant is the pre-oligodendrocytes. Hypoxia results in maturation arrest of pre-oligodendrocytes into myelin-producing oligodendrocyte.
Figure 2: Experimental design of high-throughput drug screening. A small molecule library will be screened for molecules that will promote the maturation of hypoxia-arrested pre-oligodendrocytes and induce expression of myelin proteins.
