Scientists from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have received new awards from the California Institute of Regenerative Medicine (CIRM), the state stem cell research agency, that will forward revolutionary stem cell science in medicine.

Recipients included Dr. Lili Yang, assistant professor of microbiology, immunology and molecular genetics who received $614,400  for her project to develop a novel system for studying how stem cells become rare immune cells; Dr. Denis Evseenko, assistant professor of orthopedic surgery, who received $1,146,468 for his project to identify the elements of the biological niche in which stem cells grow most efficiently into articular cartilage cells; Dr. Thomas Otis, professor and chair of neurobiology and Dr. Ben Novitch, assistant professor of neurobiology, who received $1,148,758 for their project using new light-based optigenetic techniques to study the communication between nerve and muscle cells in spinal muscular atrophy, an inherited degenerative neuromuscular disease in children; and Dr. Samantha Butler, assistant professor of neurobiology, received $598,367 for her project on discovering which molecular elements drive stem cells to become the neurons, or nerve cells, in charge of our sense of touch.

“These basic biology grants form the foundation of the revolutionary advances we are seeing in stem cell science,” said Dr. Owen Witte, professor and director of the Broad Stem Cell Research Center, “and every cellular therapy that reaches patients must begin in the laboratory with ideas and experiments that will lead us to revolutionize medicine and ultimately improve human life. That makes these awards invaluable to our research effort.”

The awards were part of CIRM’s Basic Biology V grant program, carrying on the initiative to foster cutting-edge research on significant unresolved issues in human stem cell biology. The emphasis of this research is on unravelling the secrets of key mechanisms that determine how stem cells, which can become any cell in the body, differentiate, or decide which cell they become. By learning how these mechanisms work, scientists can then create therapies that drive the stem cells to regenerate or replace damaged or diseased tissue.

Using a new method to track special immune cells

All the different cells that make up the blood come from hematopoietic or blood stem cells. These include special white blood cells called T cells, which serve as the foot soldiers of the immune system, attacking bacteria, viruses and other invaders that cause diseases. Among the T cells is a smaller group of cells called invariant natural killer T (iNKT) cells, which have a remarkable capacity to mount immediate and powerful responses to disease when activated, a small special forces unit among the foot soldiers, and are believed to be important to immune system regulation of infections, allergies, cancer and autoimmune diseases such as Type I diabetes and multiple sclerosis.

The iNKT cells develop in small numbers in the blood, usually less than 1 percent of all the blood cells, and can differ greatly in numbers between individuals. Very little is known about how the blood stem cells produce iNKT cells.

Dr. Lili Yang’s project will develop a novel model system to genetically program human blood stem cells to become iNKT cells. Dr. Yang and her colleagues will track the differentiation of human blood stem cells into iNKT cells providing a pathway to answer many critical questions about iNKT cell development.

With this knowledge, therapies can be created that increase the number of iNKT cells in the blood, creating more special forces cells and increasing the body’s ability to fight off the diseases these cells affect.

Studying the communication between nerve and muscle cells

Spinal muscular atrophy (SMA), is an inherited disease that affects children very early in development and causes atrophy or wasting away of the muscles. Children with SMA often cannot walk or move well, and because it is a progressive disease, it eventually affects the ability to breathe and is often fatal, usually before the child reaches age 10. The basic cause of the disease is a breakdown of communication between nerve cells (neurons) and the muscles they signal to initiate movement. Doctors know this communication breakdown exists, but they do not know what part of the neuron-to-muscle communication pathway breaks down.

An important use of stem cells by scientists studying particular diseases is to use the cells’ ability to become any cell in the body to grow disease models in the laboratory. Researchers can grow neurons and muscle cells that communicate in a dish in the laboratory but they have not been able to exactly pinpoint where the chain of communication breaks down in SMA.

The standard method of recording and measuring this communication is to connect a tiny electrode to the neuron, which sends an electrical signal that is received by an electrode connected to the muscle cell. Although this system works, it is slow and has not been accurate enough to allow scientists to identify the causes of SMA.

Drs. Novitch and Otis’s project uses a new technology called optigenetics to study the communication pathway between neurons and muscle cells. This amazing technique uses light to stimulate genes in the neuron that send a message to the muscle cell to contract, or the muscle cell can by infused with a special dye that lights up when signaled by the neuron. Thus a light is shone on the neuron, and the muscle cell lights up to indicate a completed signal. This method is almost instantaneous and allows the researchers to determine where in the chain the breakdown happens.

With that knowledge, therapies can be designed that directly address what goes awry between the cells, making possible novel treatments for this devastating disease.

Finding the best environment for regenerating cartilage

In his recently published work, Dr. Evseenko for the first time identified and characterized articular (joint) cartilage stem/progenitor cells at different stages of human growth, from the 5th week of fetal development to 60 years of age. This discovery is an important milestone toward a treatment that could help regenerate diseased or damaged joint cartilage. The development of such a therapy could delay or for some patients eliminate the need for joint replacement surgery.

Another step along the way to this treatment is determining what molecular elements in the body create the environment, or niche, in which cartilage develops from stem cells. The niche aids the growth of healthy cartilage cells, and helps them survive over time. Understanding the niche will help Dr. Evseenko create the best possible environment for regenerating healthy, long-lasting cartilage for therapeutic use for osteoarthritis and other diseases.

Regenerating spinal cord sensory function

The most obvious desire of those who suffer spinal cord injury is the recovery of motor function, or movement, such as the ability to walk, but these patients also lose their sense of touch and ability to feel pleasure (of holding their child) or pain (such as being burned by a hot skillet) in the affected parts of the body. Important progress has been made toward rewiring motor circuits that will permit paralyzed patients to walk, but very little progress has been made reestablishing the sensory circuits that permit patients to experience their environment through the pleasure and pain afforded by the sense of touch.

In her project, Dr. Samantha Butler seeks to understand, and eventually apply, the fundamental mechanisms that direct stem cells to become spinal sensory neurons, the spinal cord cells responsible for our sense of touch and our ability to feel pleasure and pain. Successful determination of these cell types would make possible long-term studies on neuron implantation, now in progress with stem cell-derived motor neurons, ultimately seeking to restore sensory function as well to injured patients.

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