Protecting Premature Babies from Brain Damage

The Context: It is estimated that 15 million babies are born prematurely each year, and a common premature birth complication is low oxygen levels. We know that babies born with reduced oxygen flow can show brain abnormalities, but the precise mechanisms by which low oxygen affects neural development have not been well understood.

The Study: Scientists led by NYSCF – Robertson Neuroscience Investigator Dr. Sergiu Pasca  investigated the effects of low oxygen on the developing brain by creating 3D aggregates of brain tissue from stem cells called “spheroids” and exposing the spheroids to low oxygen at a point in their development that paralleled that of an infant born prematurely. By doing this, the team identified a group of cells severely affected by reduced oxygen as well as a compound that could reverse this damage. The study appears in Nature Medicine. 

The Importance:This study sheds light on the process by which reduced oxygenation in babies born prematurely harms brain development and identifies a possible therapeutic that could reverse the effects of this damage.

Over 80% of “preemie” babies born before 25 weeks gestation have complications with brain development. A big factor in such complications is likely oxygen deprivation: preemies are often born with underdeveloped lungs or dysfunction in brain regions that control breathing, and this is thought to impact the way their brains mature.

A new study in Nature Medicine from NYSCF – Robertson Neuroscience Investigator Sergiu Pasca, MD, takes a closer look at how low levels of oxygen affect the developing brain and identifies a drug that may prevent dysfunction of a particularly susceptible group of brain cells.

Recapitulating a Preemie Brain

Dr. Pasca’s team investigated the brain development of preemies using a model they pioneered called “brain spheroids.” Brain spheroids are 3D aggregates of human brain tissue made from stem cells, and they can recapitulate the way cells interact and mature, just as they would in a human being.

The team was interested in examining the development of a brain region called the cerebral cortex. Many preemies born at least 12 weeks early have thinner cerebral cortexes than infants carried to full term, and this portion of the brain has important roles in cognition, speech, and information processing which could become dysfunctional if the region does not develop properly.

The scientists created spheroids specific to the cell types found in the cerebral cortex, and when these spheroids matured to a point that paralleled the brain of a baby at 19-24 weeks gestation, the researchers placed the spheroids in a low oxygen environment for 48 hours before restoring oxygen levels back to normal.

Attending to the Low Oxygen Response

The researchers noticed that the spheroid cells showed changes in gene expression that mimicked those seen in human brains exposed to low oxygen. They also noticed changes in gene expression of cells in the subventricular zone— a brain region whose cells help generate neurons during pregnancy. The scientists found that these cells were turning into neurons too early on, eventually causing fewer neurons to mature in total (a possible explanation for why many preemies have thinner cerebral cortexes). 

The team then tested a drug called ISRIB on the oxygen-deprived spheroids and found that it prevented cells in the subventricular zone from turning into neurons too early— suggesting that this could be a promising therapeutic for use in preemies.

Why it Matters

This study helps us better understand how oxygen deprivation harms the brains of babies born prematurely and identifies a possible therapeutic that could attend to the effects of low oxygen-related brain damage.

Finding effective therapeutics will do more than just help preemies with their early brain development. The effects of premature birth can carry into adulthood (hypoxic brain injury is often thought to lead to neurological or psychiatric disease), and preventing such damage could in turn help preemies live healthier lives in the long term.

Journal article:

Human 3D cellular model of hypoxic brain injury of prematurity.

Pașca AM, Park JY, Shin HW, Qi Q, Revah O, Krasnoff R, O’Hara R, Willsey AJ, Palmer TD, Pașca SP. Nat Med. 2019 May 6. doi: 10.1038/s41591-019-0436-0.