Two Layers of Defense

image

Every day, millions of particles from car exhaust, dirt, dust, pollen and tobacco smoke whirl in the air around us. While we inhale these unwanted microbes, how do we keep them out of our lungs? Two specialized cells in the airway play a major role.

Club cells are smooth, rounded cells that protect the inner lining (epithelium) of the airway by secreting several proteins. These proteins are able to digest or detoxify inhaled pollutants. Club cells are also stem cells, and they can divide and repair various areas of the bronchiolar epithelium.

Ciliated cells have tiny hairs (cilia), which sweep mucus up the airway where it can be coughed out or swallowed. Since the mucus traps larger particles, the ciliated cells help prevent these unwanted substances from entering the lungs and causing infection.

Image above: Club and ciliated cells from normal adult mouse airway (SEM 2800x)

Image credit: David Warburton, MD, and Gianluca Turcatel, PhD, from the Developmental Biology and Regenerative Medicine Program at The Saban Research Institute

First Step: From Human Cells to Tissue-Engineered Esophagus

image

Image: Tissue-engineered esophagus, courtesy of The Saban Research Institute

In a first step toward future human therapies, researchers at The Saban Research Institute of Children’s Hospital Los Angeles (CHLA) have shown that esophageal tissue can be grown in vivo from both human and mouse cells. The study has been published online in the journal Tissue Engineering, Part A.

The tissue-engineered esophagus formed on a relatively simple biodegradable scaffold after the researchers transplanted mouse and human organ-specific stem/progenitor cells into a murine model, according to principal investigator Tracy C. Grikscheit, MD, of the Developmental Biology and Regenerative Medicine program of The Saban Research Institute and pediatric surgeon at CHLA.

Progenitor cells have the ability to differentiate into specific types of cells, and can migrate to the tissue where they are needed. Their potential to differentiate depends on their type of “parent” stem cell and also on their niche. The tissue-engineering technique discovered by the CHLA researchers required only a simple polymer to deliver the cells, and multiple cellular groupings show the ability to generate a replacement organ with all cell layers and functions.

“We found that multiple combinations of cell populations allowed subsequent formation of engineered tissue. Different progenitor cells can find the right ‘partner’ cell in order to grow into specific esophageal cell types – such as epithelium, muscle or nerve cells – and without the need for exogenous growth factors. This means that successful tissue engineering of the esophagus is simpler than we previously thought,” said Grikscheit.

She added that the study shows promise for one day applying the process in children who have been born with missing portions of the organ, which carries food, liquids and saliva from the mouth to the stomach. The process might also be used in patients who have had esophageal cancer – the fastest growing type of cancer in the U.S. – or otherwise damaged tissue, for example from accidentally swallowing caustic substances.

“We have demonstrated that a simple and versatile, biodegradable polymer is sufficient for the growth of tissue-engineered esophagus from human cells,” added Grikscheit. “This not only serves as a potential source of tissue, but also a source of knowledge, as there are no other robust models available for studying esophageal stem cell dynamics. Understanding how these cells might behave in response to injury and how various donor cell types relate could expand the pool of potential donor cells for engineered tissue.”

Additional contributors include first author Ryan G. Spurrier, MD, Allison L. Speer, MD, Xiaogang Hou, PhD and Wael N. El-Nachef, MD, of The Saban Research Institute of Children’s Hospital Los Angeles. The study was supported by grants from the California Institute for Regenerative Medicine.

Clinical Trial Results: Patients with Leukemia Show High Remission Rates after Immunotherapy

image

Image: T cells in the blood

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, affecting over 6,000 kids and young adults each year. Approximately 90% of B-ALL patients will achieve remission through traditional treatments, such as chemotherapy and radiation. However, the majority of patients who relapse or do not respond to standard therapies die from their leukemia. In cases such as these, researchers are turning to immunotherapy, where they can “train” the body’s own immune system to attack the invading cancer cells. A recent early-phase clinical trial has shown that patients with chemotherapy-resistant B-ALL experienced high remission rates following treatment with experimental immunotherapy. The corresponding results were published on October 13 in Lancet.

“This represents a powerful new approach to treat chemotherapy-resistant ALL. The complete remission rates on this trial were significantly higher than we have seen with other new therapies tested in this population,” says Alan Wayne, MD, director of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles. Wayne headed the study during his position as clinical director of the Pediatric Oncology branch of the National Cancer Institute at the National Institutes of Health (NIH).

In this trial, investigators reprogrammed the patient’s own T cells to recognize and kill any cell with a specific protein, CD19, on its surface. CD19 is found on almost all B cells (both normal and cancerous), making it an ideal target for B-ALL immunotherapy.

Researchers also found a way to collect, modify, and grow the modified T cells in only 11 days—a crucial accomplishment since the health of patients with B-ALL can deteriorate rapidly. Investigators then went on to observe the study participants and assess the feasibility of this specific immunotherapy, determine its toxicity, and define the highest dose of the modified T cells that patients could tolerate.

Between July 2012 and June 2014, 21 patients (aged 1 to 30) who did not respond to standard chemotherapy were enrolled in the trial and infused with the modified T cells. A complete remission was observed in 14 out of the 21 patients, and 12 patients had absolutely no detectable evidence of leukemia upon completion of the tested immunotherapy.

"This is how a heart b̶r̶e̶a̶k̶s̶ forms"

image

By using a special microscope—and channeling Rob Thomas—in the Translational Biomedical Imaging Lab (TBIL) at The Saban Research Institute, Rusty Lansford, PhD, is able to record each heart cell as a living embryo grows and develops.

What am I looking at?

You are viewing the embryo from its belly (ventral) side, with the head on the left and the heart in the middle of the screen. The magenta dots are somatic cells, which will develop into various body parts. The blue dots are the cells travelling to form the inner lining of the heart chambers and blood vessels. 

Why track the movement of heart cells?

By studying heart formation on a cellular level, researchers are hoping to track exactly when and where defects arise. This will allow them to better understand and treat the progression of congenital heart diseases in infants and children.

Contact Children’s Hospital Los Angeles Research Communications
rescomm@chla.usc.edu or (323) 361-1812