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New Hope for Babies Affected by Birth Asphyxia

Research shows promise in stem cell treatments for babies with birth asphyxia.

Inês Caramelo, Sandra I. Anjo, Vera M. Mendes, Ivan L. Salazar, Alexandra Dinis, Carla M.P. Cardoso, Carlos B. Duarte, Mário Grãos, Bruno Manadas

― 8 min read


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Table of Contents

Birth asphyxia is a serious condition that happens when a newborn doesn't get enough blood or oxygen during birth. This can cause a variety of problems, especially affecting the brain, which needs a lot of energy and doesn’t have much stored up. Parents hearing this may feel their hearts sink, since brain damage can lead to many other issues, including conditions like cerebral palsy or other disabilities.

The Vulnerability of the Brain

Newborns are not like adults. Their brains are still in a very delicate state, making them more prone to damage from any lack of oxygen. The World Health Organization points out that birth asphyxia is one of the top reasons for child deaths and disabilities around the globe. It's not just a minor issue; more than half of the babies who survive the initial injury may end up facing serious challenges in their early years, like seizures, motor problems, and other health complications.

What Happens After Asphyxia?

When asphyxia occurs, there’s usually a lack of energy at first. But after that, blood flow may get restored, which is a good thing, right? Well, it turns out there’s a catch. During the time without proper oxygen, the brain starts to use energy in a way that creates a lot of lactic acid and reduces a crucial molecule called ATP. Think of ATP like the battery that keeps everything running smoothly in your body. When this battery runs low, other problems arise.

As the brain becomes starved of energy, there is too much sodium and calcium inside brain cells, leading to a chaotic situation known as neurotransmitter release, which is like setting off fireworks in the brain. It can lead to excitotoxicity, where too many signals can damage brain cells. The brain cells swell up and may suffer from oxidative stress, which is basically the oxidative equivalent of having too many dirty dishes piling up because you didn't wash them after dinner.

The Damage Doesn't End Immediately

After the initial damage, the problems don’t just vanish. Many brain cells may seem to recover at first but can later die due to a delayed energy failure. The whole process can stretch out over several days, with secondary injuries happening even after the initial lack of oxygen. Over time, chronic inflammation and changes in gene activity can further complicate the situation, leading to long-term issues that can last for months or even years.

Current Treatments: Therapeutic Hypothermia

Right now, one of the main treatments for newborns facing moderate to severe Hypoxic-ischemic Encephalopathy (HIE) is therapeutic hypothermia. Basically, this involves cooling the baby’s body temperature down to a specific range for a limited time. Think of it as giving the brain a much-needed break to slow things down and recover. While this treatment can help reduce inflammation and cell death, it doesn’t always work perfectly.

The Promise of Stem Cells

Recently, researchers have been looking at stem cells as a new treatment option. These unique cells have some pretty remarkable abilities. They can help generate new brain cells and reduce inflammation. Scientists found that by making stem cells feel like they’re in a more comfortable environment, they can become even more effective.

In this study, scientists used special growing conditions to prepare stem cells before testing them on brain cells that had been starved of oxygen. By mimicking the conditions that these cells would normally grow in, researchers made them more potent.

Setting Up the Experiment

To test the effects of these specially prepared stem cells, scientists created an in vitro model that simulates the conditions of birth asphyxia. They took brain cells from rat embryos, treated them to mimic oxygen deprivation, and then monitored how well they fared after being treated with normal or specially prepared stem cells.

After they damaged the brain cells with oxygen deprivation, they looked for signs of recovery in both groups of cells. They wanted to see if the specially treated stem cells could help restore the brain network affected by asphyxia.

Culturing the Brain Cells

To isolate the brain cells, researchers first prepared rat embryos in a specific way. They used a special solution to separate the cells and placed them in a suitable environment to help them grow for about a week. This gave the cells time to mature before exposing them to a simulated lack of oxygen.

Once the cells were ready, they subjected them to low oxygen levels and monitored how they handled the stress. The scientists then treated some of the cells with the special stem cells to see if they could help the stressed-out brain cells recover.

Preparing the Stem Cells

The stem cells used in the experiments came from umbilical cords, which are a rich source of these amazing cells. Researchers expanded these cells in a lab until they had enough to work with. They tested both regular cultures and cultures that more closely resembled the conditions found in the human body, i.e., soft surfaces and specific oxygen levels.

After letting the cells grow for a day, they collected the substances those stem cells released into their environment, knowing that these substances (the secretome) would hold the key to their potential benefits.

The Oxygen Glucose Deprivation Insult

When the brain cells were subjected to five hours of low oxygen and glucose levels, the researchers made sure to monitor the situation closely. They replaced the medium with one lacking glucose to induce conditions similar to birth asphyxia. The control group, on the other hand, was given a regular environment to thrive in.

After the oxygen deprivation, the researchers wanted to see how the brain cells fared. They looked at the levels of various proteins to evaluate whether the stem cell treatment helped restore normal levels in these brain cells.

Assessing Neuronal Health

After the brain cells were subjected to the stressful conditions, researchers conducted tests to examine cell health. They confirmed that the oxygen-starved brain cells were not doing well, as indicated by the loss of protein markers that signify a healthy neuronal structure.

The Effects of Stem Cell Treatment

After exposing the stressed brain cells to the secretome from both the regular and the specially prepared stem cells, researchers noticed some interesting effects. Compared to the regular stem cell treatment, those treated with the specially prepared secretome had fewer signs of cell death.

Using advanced imaging and analysis methods, they were able to confirm that the secretome was helping keep the brain cells healthier, stabilizing their structure even after an oxygen shortage.

The Secret Sauce: Secretome Analysis

When analyzing the secretome-the mix of substances released by stem cells-the researchers found a treasure trove of proteins. They were particularly interested in those that might help restore cellular functions. Many proteins linked to injury recovery, inflammation management, and overall cell health were identified.

By comparing the effects of the specially prepared secretome with the regular one, scientists could better understand which proteins were doing the heavy lifting in the recovery process. This analysis helped them realize that these nutritionally rich substances could play a crucial role in protecting brain cells.

Finding Common Ground: Mechanisms of Action

After studying the outcomes, researchers realized that both types of treatments triggered a few similar responses in the brain cells. One of the primary responses involved improving how proteins were made. These proteins play critical roles in keeping cells healthy, especially in the wake of an injury.

In particular, a special protein called L13a, which helps regulate how other proteins are made, was a key player. This was an exciting discovery since keeping the production of proteins balanced is crucial for cell survival.

The Role of Mitochondria

Mitochondria are the powerhouses of cells, providing the energy needed for all cellular activities. Researchers found that the special secretome treatment had an impact on these little energy factories. By restoring the function of mitochondrial proteins, the special treatment potentially helped prevent the second wave of damage often seen following initial injury.

The Aftermath of Treatment

After being treated with the various Secretomes, the brain cells showed signs of resilience. They were better at maintaining their shapes and connections with one another. The positive effects of the specially prepared secretome were evident in the ability of the brain cells to restore their functionality even after the trauma.

What’s Next?

The potential that stem cells have for treating conditions like birth asphyxia is an exciting area of research. Scientists are eager to expand upon these findings in future studies to better understand how to harness this therapeutic approach effectively.

Innovative treatments like this could lead to improved care for newborns facing the consequences of oxygen deprivation at birth. Researchers continue to investigate ways of refining stem cell treatments so they can work even better in clinical settings.

In summary, while birth asphyxia can lead to significant challenges for newborns, promising treatments are on the horizon. The understanding of how stem cells and their secretome can protect and enhance brain health is growing, paving the way for better outcomes in the future.

Original Source

Title: Physioxia-modulated mesenchymal stem cells secretome has higher capacity to preserve neuronal network and translation processes in hypoxic-ischemic encephalopathy in vitro model

Abstract: Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of child death worldwide. Most of the survivors develop various neurological diseases, such as cerebral palsy, seizures, and/or motor and behavioral problems. HIE is caused by an episode of perinatal asphyxia, which interrupts the blood supply to the brain. Due to its high energy demands, this interruption initiates glutamate excitotoxic pathways, leading to cell death. Umbilical cord mesenchymal stem cells (UC-MSCs) are gaining attention as a promising complement to the current clinical approach, based on therapeutic hypothermia, which has shown limited efficacy. Previous data have shown that priming MSCs under physiological culture conditions, namely soft platforms (3kPa) - mechanomodulated - or physiological oxygen levels (5% O2) - physioxia - leads to changes in the cellular proteome and their secretome. To evaluate how exposing MSCs to these culture conditions could impact their therapeutic potential, physiologically primed UC-MSCs or their secretome were added to an in vitro HIE model using cortical neurons primary cultures subjected to oxygen and glucose deprivation (OGD) insult. By comparing the neuronal proteome of sham, OGD insulted, and OGD-treated neurons, it was possible to identify proteins whose levels were restored in the presence of UC-MSCs or their secretome. Despite the different approaches that differentially altered UC-MSCs proteome and secretome, the effects converged on the re-establishment of the levels of proteins involved in translation mechanisms (such as the 40S and 60s ribosomal subunits), possibly stabilizing proteostasis, which is known to be essential for neuronal recovery. Interestingly, treatment with the secretome of UC-MSC modulated under physioxic conditions sustained part of the neuronal network integrity and modulated several mitochondrial proteins, including those proteins involved in ATP production. This suggests that the unique composition of the physioxia-modulated secretome may offer a therapeutical advantage in restoring essential cellular processes that help neurons maintain their function, compared to traditionally expanded UC-MSCs. These findings suggest that both the presence of UC-MSCs and their secretome alone can influence multiple targets and signaling pathways, collectively promoting neuronal survival following an OGD insult.

Authors: Inês Caramelo, Sandra I. Anjo, Vera M. Mendes, Ivan L. Salazar, Alexandra Dinis, Carla M.P. Cardoso, Carlos B. Duarte, Mário Grãos, Bruno Manadas

Last Update: 2024-11-27 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.11.26.625525

Source PDF: https://www.biorxiv.org/content/10.1101/2024.11.26.625525.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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