UCLA scientists make sensory nerves from human stem cells for the first time

Being able to tell the difference between hot and cold or feeling the embrace of a loved one are experiences that many of us take for granted in our daily lives. But paralyzed patients who have lost their sense of touch don’t have this luxury.

Sensory nerves are cells in the spinal cord that send signals from outside of the body to the brain where they are translated into senses like touch, temperature and smell. When someone is paralyzed, their sensory nerves can be damaged, preventing these sensory signals from reaching the brain and leaving patients at risk for severe burns or not knowing when they’ve cut themselves because they can’t feel the pain.

A Journey to Restore Touch

A group of scientists led by Dr. Samantha Butler at the  Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA are on a research journey to restore the sense of touch in paralyzed patients and people with sensory neuron damage. In their earlier work, which we blogged about back in September, the team discovered that signaling proteins called BMPs played an important role in the development of sensory nerve cells in chicken embryos.

With the help of CIRM-funding, Butler and her team have made significant progress since this earlier study, and today, we bring you an exciting update on their latest findings published in the journal Stem Cell Reports.

Using a similar strategy to their previous study, Butler and her team attempted to make sensory nerve cells from human stem cells in a dish. They exposed human pluripotent stem cells to a specific BMP protein, BMP4, and a chemical called retinoic acid. This combination treatment created two types of sensory nerve cells: Dl1 cells, which allow you to sense your body’s position and movement, and Dl3 cells, which allow you to feel pressure.

Human embryonic stem cell-derived neurons (green) showing nuclei in blue. Left: with retinoic acid added. Right: with retinoic acid and BMP4 added, creating proprioceptive sensory nerve cells (pink). (Image source: UCLA Broad Stem Cell Research Center/Stem Cell Reports)

This is the first time that researchers have reported the ability to make sensory nerve cells from human stem cells. Another important finding was that the UCLA team was able to make sensory nerve cells from both human embryonic stem cells and human induced pluripotent stem cells (iPSCs), which are pluripotent stem cells derived from a patient’s own cells. The latter finding suggests a future where paralyzed patients can be treated with personalized cell-based therapies without the need for immune suppressing drugs.

Feeling the Future

This study, while still in its early stages, is an important step towards a future where paralyzed patients can regain feeling and their sense of touch. Restoring a patient’s ability to move their limbs or walk has dominated the field’s focus, but Butler argues in a UCLA news release that restoring touch is just as important:

Samantha Butler

“The field has for a long time focused on making people walk again. Making people feel again doesn’t have quite the same ring. But to walk, you need to be able to feel and to sense your body in space; the two processes really go hand in glove.”

 

Butler and her team are continuing on their journey to restore touch by transplanting the human sensory nerve cells into the spinal cords of mice to determine whether they can incorporate into the spine and function properly. If the transplanted cells show promise in animal models, the team will further develop this cell-based therapy for clinical trials.

Butler concluded,

“This is a long path. We haven’t solved how to restore touch but we’ve made a major first step by working out some of these protocols to create sensory interneurons.”

Grafted Stem Cells Snake through Spinal Cord, CIRM-Funded Study Finds

New research lends increasing support to the notion that paralysis may not be so permanent after all.

Scientists at the University of California, San Diego have generated stem cells that, when grafted onto the injured spines of rats—traverse through the injury sites, coupling with nerve cells hidden beneath the damaged tissue. These results, published today in the journal Neuron, are a critical next step towards using stem cell-technology to reverse spinal cord injury—a condition that has long been considered irreversible.

The extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury. [Credit: UCSD School of Medicine

The extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury. [Credit: UCSD School of Medicine]

This research team, led by CIRM grantee Dr. Mark Tuszynski, generated stem cells from the skin cells of an adult human male. These so-called induced pluripotent stem cells, or iPS cells, then had the ability to transform into virtually any cell type. With a bit of coaxing, the team transformed them one more time—into early-stage neurons—and grafted them onto the injured rats. After monitoring the animals over a period of three months, what they began to see astonished them.

The most amazing changes came from the cells’ axons—long, spindly projections that connect neurons to each other, allowing them to communicate through transmission of electrical signals. Much to their surprise, the team saw these iPS cell-derived axons began to grow—some extending across the animals’ entire central nervous system.

But it wasn’t just the fact that the axons grew that excited researchers—it’s where they went. They began to pierce through the spinal injury sites, penetrating scar tissue and grey matter and forming connections with existing rat neurons that had been entombed inside. Even more incredibly, the native rat axons began to do the same—growing and piercing through the iPS cell grafts to form connections of their own.

As Tuszynski explained in a news release:

“These findings indicate that intrinsic neuron mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons that have been reprogrammed.”

The results of this study are encouraging, say the research team, though they do raise a few questions about the underlying signaling mechanisms that are guiding these axons to grow and become intertwined. Tuszynski elaborated:

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible side effects if axons are mis-targeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame—months to years—or more rapidly.”

The researchers are now exploring whether using different types of stem cells, such as embryonic stem cells, would yield similar results. Once they hone in on the best method, they hope to take their findings further down the path towards clinical trials.

“Ninety-five percent of human clinical trials fail,” explained Tuszynski. “We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”