3D brain model shows potential for treatment of hypoxic brain injuries in infants

Image of 3D brain cultures in the Sergiu Pasca lab.
Photo courtesy of Timothy Archibald.

A baby’s time in the womb is one of the most crucial periods in terms of its development. The average length of gestation, which is defined as the amount of time in the womb from conception to birth, is approximately 40 weeks. Unfortunately, for reasons not yet fully understood, there are times that babies are born prematurely, which can lead to problems.

These infants can have underdeveloped portions of the brain, such as the cerebral cortex, which is responsible for advanced brain functions, including cognition, speech, and the processing of sensory and motor information. The brains of premature infants can be so underdeveloped that they are unable to control breathing. This, in combination with underdeveloped lungs, can lower oxygen levels in the blood, which can lead to hypoxic, or low oxygen related, brain injuries.

In a previous study, doctors Anca and Sergiu Pasca and their colleagues at Stanford developed a technique to create a 3D brain that mimics structural and functional aspects of the developing human brain.

Using this same technique, in a new study with the aid of CIRM funding, the team grew a 3D brain that contained cells and genes similar to the human brain midway through the gestational period. They then exposed this 3D brain to low oxygen levels for 48 hours, restored the oxygen level after this time period, and observed any changes.

It was found that progenitor cells in a region known as the subventricular zone, a region that is critical in the growth of the human cortex, are affected. Progenitor cells are “stem cell like” cells that give rise to mature brain cells such as neurons. They also found that the progenitor cells transitioned from “growth” mode to “survival” mode, causing them to turn into neurons sooner than normal, which leads to fewer neurons in the brain and underdevelopment.

In a press release, Dr. Anca Pasca is quoted as saying,

“In the past 20 years, we’ve made a lot of progress in keeping extremely premature babies alive, but 70% to 80% of them have poor neurodevelopmental outcomes.”

The team then tested a small molecule to see if it could potentially reverse this response to low oxygen levels by keeping the progenitor cells in “growth” mode. The results of this are promising and Dr. Sergiu Pasca is quoted as saying,

“It’s exciting because our findings tell us that pharmacologically manipulating this pathway could interfere with hypoxic injury to the brain, and potentially help with preventing damage.”

The complete findings of this study were published in Nature.

The best scientists always want to know more

Sir Isaac Newton

Sir Isaac Newton

Some years ago I was in the Wren Library at Trinity College, Cambridge in England when I noticed a display case with a cloth over it. Being a naturally curious person, downright nosy in fact, I lifted the cloth. In the display case was a first edition of Sir Isaac Newton’s Principia Mathematica and in the margins were notes, corrections put there by Newton for the second edition.

It highlighted for me how the best scientists never stop working, never stop learning, never stop trying to improve what they do.

That came back to me when I saw a news release from ViaCyte, a company we are funding in a Phase 1 clinical trial to treat type 1 diabetes.  The news release announced results of a study showing that insulin-producing cells, created in the lab from embryonic stem cells, can not only mature but also function properly after being implanted in a capsule-like device and placed under the skin of an animal model.

VC-01-cross-section-5

Now the clinical trial we are funding with ViaCyte uses a similar, but slightly different set of cells in people. The device in the trial contains what ViaCyte calls PEC-01™ pancreatic progenitor cells. These are essentially an earlier stage of the mature pancreatic cells that our body uses to produce insulin. The hope is that when implanted in the body, the cells will mature and then behave like adult pancreatic cells, secreting insulin and other hormones to keep blood glucose levels stable and healthy.

Those cells and that device are being tested in people with type 1 diabetes right now.

Learning more

But in this study ViaCyte wanted to know if beta cells, a more mature version of the cells they are using in our trial, would also work or have any advantages over their current approach.

The good news, published in the journal Stem Cells Translational Medicine,  is that these cells did work. As they say in their news release:

“The animal study also demonstrated for the first time that when encapsulated in a device and implanted into mice, these more mature cells are capable of producing functional pancreatic beta cells. ViaCyte is also the first to show that these further differentiated cells can function in vivo following cryopreservation, a valuable process step when contemplating clinical and commercial application.”

This does not mean ViaCyte wants to change the cells it uses in the clinical trial. As President and CEO Paul Laikind, PhD, makes clear:

“For a number of reasons we believe that the pancreatic progenitor cells that are the active component of the VC01 product candidate are better suited for cell replacement therapy. However, the current work has expanded our fundamental knowledge of beta cell maturation and could lead to further advances for the field.”

And that’s what I mean about the best scientists are the ones who keeping searching, keeping looking for answers. It may not help them today, but who knows how important that work will prove in the future.