Assembloids with migrating interneurons. Image credit: Alyssa Puno (CCBY 4.0)
Medical advances have significantly improved the survival of preterm and extremely preterm babies (less than 28 weeks of pregnancy). However, no therapies yet exist to prevent brain injury that is often associated with preterm birth, often leading to lifelong neurological and psychiatric disorders.
Over the past few decades, research studies have used rodent models to try to identify therapeutics. But when it came to testing in humans, therapies that looked promising in rodents failed to show benefit in patients, suggesting possible interspecies differences and the need to study human cells. While this has been challenging in the past, recent major scientific advances now allow the generation of human brain cells from stem cells, which have themselves been derived from human skin or blood cells.
Clinical studies have shown that hypoxia – oxygen deprivation of the brain – is a major risk factor for brain injury of prematurity. Brain tissue studies of people previously born preterm have shown a decrease in the number of grey matter inhibitory neurons, which help prevent overactivity in the healthy brain, such as seizures. During fetal development, these cells migrate long distances to reach their final location for optimal activity. Puno et al. tested whether hypoxia affects the migration of inhibitory neurons and if any damage could be reversed. They used human brain assembloids, which are three-dimensional clumps of brain cells that recreate the cell-migration process in a laboratory dish.
Puno et al. found that hypoxia significantly decreases the migration of inhibitory neurons and that this injury persists even after re-adding oxygen to the cells. Using advanced research tools, they found that a protein called adrenomedullin increases in the organoids in response to hypoxia, but due to a lack of oxygen it cannot be modified to make it functional. However, adding more functional adrenomedullin to the cells during hypoxia restores migration.
Puno et al. show for the first time that migration of inhibitory neurons is affected by hypoxia. They identify adrenomedullin as a potential target for developing effective therapies for premature babies, which may also be relevant for adults with hypoxic brain injuries such as stroke. Further studies in animal models that are more similar to humans are needed to confirm adrenomedullin’s safety, dosage and mechanism of action.
