‘Mini lung’ model shows scientists early stages of new coronavirus infection

Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green)
Image Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong

The development of organoid modeling has significantly expanded our understanding of human organs and the diseases that can affect them. For those unfamiliar with the term, an organoid is a miniaturized, simplified version of an organ produced that is also three dimensional.

Recently, scientists from the University of Cambridge and the Korea Advanced Institute Science and Technology (KAIST) were able to develop ‘mini lungs’ from donated tissue and use them to uncover the mechanisms behind the new coronavirus infection and the early immune response in the lungs.

SARS-CoV-2, the name of the coronavirus that causes COVID-19, first appears in the alveoli, which are tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide.

To better understand how SARS-CoV-2 infects the lungs and causes COVID-19, the team used donated tissue to extract a specific type of lung cell. They then reprogrammed these cells to an earlier stem cell-like state and used them to grow the lung organoids.

The team then infected the ‘mini lungs’ with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 after traveling to Wuhan, China.

Within the newly infected lung organoids, the team observed that the virus began to replicate rapidly, reaching full cellular infection in just six hours. Replication allows the virus to spread the infection throughout the body to other cells and tissue. The infected cells also began to produce interferons, which are proteins that act as warning signals to healthy cells, telling them to activate their antiviral defenses. After two days, the interferons triggered an immune response and the cells started fighting back against infection. Two and a half days after infection, some of the alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

In a news release, Dr. Joo-Hyeon Lee, co-senior author of this study, elaborates on how he hopes this study can help more vulnerable sections of the population.

“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue.”

The complete study was published in Cell Stem Cell.

CIRM has funded two discovery stage research projects that use lung organoids to look at potential treatments for COVID-19. One is being conducted by Dr. Brigitte Gomperts at UCLA and the other by Dr. Evan Snyder at the Sanford Burnham Prebys Medical Discovery Institute.

Two UCLA scientists receive CIRM funding for discovery research for COVID-19

Dr. Brigitte Gomperts (left) and Dr. Gay Crooks (right), UCLA
Image Credit: UCLA Broad Stem Cell Center

This past Friday, the CIRM Board approved funding for its first clinical study for COVID-19. In addition to this, the Board also approved two discovery stage research projects, which support promising new technologies that could be translated to enable broad use and improve patient care. Before we go into more detail, the two awards are summarized in the table below:

The discovery grant for $150,000 was given to Dr. Gay Crooks at UCLA to study how specific immune cells called T cells respond to COVID-19. The goal of this is to inform the development of vaccines and therapies that harness T cells to fight the virus. Typically, vaccine research involves studying the immune response using cells taken from infected people. However, Dr. Crooks and her team are taking T cells from healthy people and using them to mount strong immune responses to parts of the virus in the lab. They will then study the T cells’ responses in order to better understand how T cells recognize and eliminate the virus.

This method uses blood forming stem cells and then converts them into specialized immune cells called dendritic cells, which are able to devour proteins from viruses and chop them into fragments, triggering an immune response to the virus.

In a press release from UCLA, Dr. Crooks says that, “The dendritic cells we are able to make using this process are really good at chopping up the virus, and therefore eliciting a strong immune response”

The discovery grant for $149,998 was given to Dr. Brigitte Gomberts at UCLA to study a lung organoid model made from human stem cells in order to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with COVID-19. Dr. Gomberts will be testing drugs that have been approved by the U.S. Food and Drug Administration (FDA) for other purposes or have been found to be safe in humans in early clinical trials. This increases the likelihood that if a successful drug is found, it can be approved more rapidly for widespread use.

In the same press release from UCLA, Dr. Gomberts discusses the potential drugs they are evaluating.

“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible.”

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.