Better ‘Mini Brains’ Could Help Scientists Identify Treatments for Zika-Related Brain Damage

UCLA researchers develop improved technique for creating brain tissue from stem cells

UCLA researchers have developed an improved technique for creating simplified human brain tissue from stem cells. Because these so-called “mini brain organoids” mimic human brains in how they grow and develop, they’re vital to studying complex neurological diseases.

In a study published in the journal Cell Reports, the researchers used the organoids to better understand how Zika infects and damages fetal brain tissue, which enabled them to identify drugs that could prevent the virus’s damaging effects.

The research, led by senior author Ben Novitch, could lead to new ways to study human neurological and neurodevelopmental disorders, such as epilepsy, autism and schizophrenia.

“Diseases that affect the brain and nervous system are among the most debilitating medical conditions,” said Novitch, UCLA’s Ethel Scheibel Professor of Neurobiology and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Mini brain organoids provide us with opportunities to examine features of the human brain that are not present in other models, and we anticipate that their similarity to the real human brain will enable us to test how various drugs impact abnormal or diseased brain tissue in far greater detail.”

For about five years, scientists have been using human pluripotent stem cells, which can create any cell type in the body, to develop mini brain organoids. But the organoids they produced have generally been difficult to use for research because they had highly variable structures and inconsistent cellular composition, and because they didn’t correctly mimic the layered structure of the brain and were too small — often no bigger than the head of a pin. They also didn’t survive very long in the laboratory and contained neural tissue that was difficult to classify in relation to real human brain tissue.

The organoids developed by Novitch’s group have a stratified structure that accurately mimics the human brain’s onion-like layers, they survive longer and have a larger and more uniform shape.

To create the brain organoids, Novitch and his team made several modifications to the methods that other scientists used previously: The UCLA investigators used a specific number of stem cells and specialized petri dishes with a modified chemical environment; previous methods used varying amounts of cells and a different type of dish. And they added a growth factor called LIF, which stimulated a cell-signaling pathway that is critical for human brain growth.

The researchers found critical similarities between the organoids they developed and real human brain tissue. Among them: The organoids’ anatomy closely resembled that of the human cortex, the region of the brain associated with thought, speech and decision making; and a diverse array of neural cell types commonly found in the cortex were all present in the organoids, and they exhibited electrical activities and network function, meaning they were capable of communicating with one another much like the neural networks in the human brain do.

The UCLA scientists also found that they could modify their methodology to make other parts of the brain including the basal ganglia, which are involved in the control of movement and are affected by neurodegenerative conditions such as Parkinson’s disease and Huntington’s disease.

“While our organoids are in no way close to being fully functional human brains, they mimic the human brain structure much more consistently than other models,” said Momoko Watanabe, a UCLA postdoctoral fellow and the study’s first author. “Other scientists can use our methods to improve brain research because the data will be more accurate and consistent from experiment to experiment and more comparable to the real human brain.”

When the team exposed the organoids to Zika, they discovered specifically how the virus destroys neural stem cells, the cells from which the brain grows during fetal development. Novitch’s team found that there are four specific molecules, called receptors, on the outer surface of neural stem cells; previous studies have indicated that the Zika virus could bind to these receptors and infect the cells. The researchers then mapped the changes that occur in the neural stem cells after Zika infection, presenting a clearer picture of how the virus infiltrates and harms fetal brain tissue.

Zika is associated with an unusually high incidence of fetal brain damage, so understanding how neural stem cells are affected by the virus could be an important new step toward a treatment.

The researchers tested several drugs on the Zika-infected organoids. They found three that are effective at blocking the virus’s entry into the brain tissue, including two that protected neural stem cells by preventing the interaction between the virus and entry receptors on the neural stem cells. In previous studies by Novitch and other UCLA colleagues, one of those drugs reduced brain damage in fetal mice infected with Zika.

“Many neurological diseases or conditions arise from defects in the way one neuron communicates with another or from the way an external factor, such as a virus, interacts with neural cells,” Novitch said. “If we can focus in at the level of cellular communication, we should be able to model those undesirable cellular interactions and counteract them with drugs or other therapies.”

The team plans to continue using its improved organoids to better understand human brain development and to learn more about autism spectrum disorders, epilepsy and other neurological conditions.

The experimental drugs used in the preclinical study have not been tested in humans or approved by the Food and Drug Administration for treating Zika in humans.

University Hospitals Rainbow Babies & Children’s Hospital Opens First Stem Cell Study in Patients with Cystic Fibrosis

Study is first step toward goal of developing therapy to quell CF’s lung inflammation

A 39-year-old man with cystic fibrosis (CF) made history by becoming the first person to receive human adult stem cells in a new research study that researchers hope will someday lead to the development of a therapy to reduce the inflammation and infection caused by CF.

The pioneering subject in the study is Bob Held from Alliance, Ohio, who on Jan. 26 received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers. Mr. Held was diagnosed with CF when he was 16 months old.

Currently, there is no cure for CF, and life expectancy for patients who survive into adulthood is approximately 41 years of age.

“It was a very exciting day for us with the very first participant in the first stem cell trial for cystic fibrosis,” said James Chmiel, MD, the principal investigator of the study at University Hospitals Rainbow Babies & Children’s Hospital.

The Phase 1 trial will assess the safety and tolerability of hMSCs in adult patients with CF.

“This is an early phase trial, and the most important thing is to ensure safety,” said Dr. Chmiel. “This study consists of a single infusion of stem cells. We will follow the study participants for a year to make sure it’s safe. Before applying any therapy on a broad basis, we want to make sure that it’s safe.”

While the goal of the study is safety, Dr. Chmiel hopes this is a first step towards the ultimate goal of developing a therapy to reduce lung inflammation and infection, resulting in longer and healthier lives for people with CF.

“While there’s been a tremendous increase in survival for people with CF from when I entered the field in the 1990s, that’s still not good enough,” said Dr. Chmiel, Director of the Cystic Fibrosis Therapeutics Development Center at UH Rainbow Babies & Children’s Hospital and Professor of Pediatrics at Case Western Reserve University School of Medicine. “While we’ve made great progress, we still have a long way to go.”
The stem cells that Mr. Held received were collected from the bone marrow of a healthy adult volunteer. UH is a national leader in the use of stem cell therapy with hMSCs. Researchers from UH, along with the CWRU School of Medicine, discovered hMSCs. The hMSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases, and they possess natural abilities to detect changes in their environment, such as inflammation. The hope is that hMSCs can reduce the inflammation in the lungs caused by CF.

CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.

“One of the issues in CF is that people with the disease get bacterial infections in their lungs, and these bacteria incite a vigorous and excessive inflammatory response,” explained Dr. Chmiel. “It’s actually the body’s inflammatory response that damages the lungs. The inflammatory response tries to eliminate the bacteria, but it’s not successful. Instead, the inflammatory system releases molecules that damage the individual’s own airways. The lung disease causes much of the illness and is responsible for the majority of the mortality of the disease.”

The stem cells are donated by healthy adult volunteers who go through a rigorous screening process. The stem cells are cultured in the UH stem cell facility. Volunteers with CF who are in the study receive an infusion through an IV.
“Once in the patient’s body, the stem cell tracks to the area where there’s a significant amount of inflammation, and they take up residence there. The stem cells then respond to the environment, and hopefully reverse some of the abnormalities,” said Dr. Chmiel. “We hope in future studies to demonstrate that the stem cells reduce the infection and inflammation and return the lungs to a more normal state.”

“This therapy aims to turn down the inflammatory response, not eliminate it because we still have to keep the bacteria in check. We want to reduce inflammation and the subsequent lung damage caused by inflammation without allowing the bacteria to proliferate,” said Dr. Chmiel.

A total of 15 clinically stable adults with CF will be enrolled in the study. Support for the study is from the Cystic Fibrosis Foundation.

The patient, Mr. Held, considers himself fortunate to be close to 40 with CF. When he was growing up, he said he’d miss 50 days of school each year because of the disease. Every day, he needs to breathe in aerosols for about two hours in the morning and 1-1/2 hours before bed to keep his lungs functioning. While he hasn’t been sick from the illness since his late teens, he does check himself into the hospital a couple of times a year for precautionary measures and to prevent himself from “getting into a valley” with CF.

His late wife, Michelle, died of CF seven years ago. They had met when they were kids, but didn’t get married until 2012. She died from the disease suddenly 28 days after they married.

“My only regret is that I didn’t ask her out sooner,” said Mr. Held.
He is participating in the study to carry on Michelle’s legacy, and “I am hoping the future generations of CF patients can get better treatments and that eventually a cure will be found for them,” he said.

First Skin-to-Eye Stem Cell Transplant in Humans Successful

Researchers have safely transplanted stem cells derived from a patient’s skin to the back of the eye in an effort to restore vision. The research is being presented at the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) this week in Seattle, Wash.

A small piece of skin from the patient’s arm was collected and modified into induced pluripotent stem cells (iPSC). The iPSCs were then transformed into eye cells, which were transplanted into the patient’s eye. The transplanted cells survived without any adverse events for over a year and resulted in slightly improved vision. The patient suffered from advanced wet age-related macular degeneration (AMD) that did not respond to current standard treatments.

iPSCs are adult cells that have been reprogrammed to an embryonic stem cell-like state, which can then be differentiated into any cell type found in the body.