Institute researchers identify three key roadblocks to stem cell therapies
August 21, 2023
As the stem cell sciences progresses rapidly, we are drawing ever closer to a world in which once uncurable diseases and conditions will find treatments. But a recent review by researchers at the Institute for Stem Cell Biology and Regenerative Medicine, New York University and Harvard have identified three key roadblocks to developing discoveries into therapies: fibrosis, immune activity, and cell over-proliferation.
“What was once considered the future of medicine is now becoming a reality,” said Michael Longaker, MD. “But to get to that new reality we have to be able to overcome these significant hurdles.”
Longaker and his colleagues observe that nearly every human malady, be it injury, chronic disease, or degenerative disease, damages tissues in the body. The body has the capacity to heal itself, to regenerate the tissues that have been damaged, but often inflammation and fibrosis (the development of scar tissue) interferes with that regenerative process. In fact, 45% of all deaths can be traced to regenerative failures caused by inflammation and fibrosis.
“I was shocked by that statistic,” Longaker said. “Following heart attack, inflammatory bowel disease, liver disease, you name it---most organs in the human body fall short of complete repair after injury.”
Longaker began his career decades ago studying how scarring did not occur in the fetus, and has since continued to study why scar tissues develop or do not. “Scars are a kind of spot-weld in the skin—a quick repair that lets the person continue to survive and procreate, even though the tissue might not function quite as well as before.” But in many cases, reduction in function caused by scar tissue can lead to major problems over time. The stiffening of heart tissue caused by scarring after a heart attack make the heart muscles work harder to pump the same amount of blood, setting off a reinforcing cycle that can eventually lead to heart failure.
By studying the underlying biology of scar formation, however, Longaker and his colleagues have discovered how to interfere with the signals that put cells on a path to become fibroblasts (scar tissues). With that pathway blocked, normal skin will regenerate where a scar would otherwise form.
“Regeneration turns out to be the default pathway if you block other options, like fibrosis,” Longaker said.
Inflammation brings its own challenges, the researchers found. Inflammation is a complex response to injury by the immune system. Inflammation is largely a beneficial process that is needed to fight off invading organisms. May of the inflammatory signals are also necessary to start and maintain the regenerative process.
But inflammation can also promote fibrosis on its own, the researchers said. “Precisely targeting inflammation may ameliorate fibrosis and unlock latent regenerative capacity,” Longaker said.
The immune system is also a roadblock to promise that stem cell transplants might help injured tissues repair themselves. Unless the implanted stem cells come from the patient’s own body, the immune system is designed to recognize them as foreign invaders and attack. Currently, this attack is controlled by strong immunosuppressive medications, but these therapies have their own problems.
“The good news is that many scientists, including some in the institute such as Agnieszka Czechowicz, are currently studying ways to carefully recreate the immune system so that it doesn’t attack transplanted tissues and cells.
Lastly, there is the roadblock of cell over-proliferation. “When you transplant stem cells, there is always the worry that those cells may proliferate more than you want and in a disorganized fashion,” Longaker said. Such uncontrolled growth can result in a non-cancerous mass of tissue that can interfere with bodily functions. If that were to happen to neural stem cells transplanted into the spinal cord, for instance, the resulting teratoma could squeeze the spinal column and cause paralysis.
“We can think of stem cells as seeds that we plant in the “soil” of the body,” Longaker said. “We need to think not only about the nature of the cell we are implanting, but also about the environment that the cell is going into, the ‘soil’ that will support and nurture that seed and help it grow.”
Stem cells often operate in a complex “niche,” a cradle of non-stem cells that provide key signals and support. “If you put stem cells in a hostile “soil,” you don’t get what you want. Understanding the supportive environment and the key signals that each kind of stem cell needs will be essential to overcoming this roadblock, the researchers say.
“The more we understand the better,” Longaker said. “I’m optimistic because we are now understanding these roadblocks and have potential therapies to address all of them.”
“Further understanding will require an interdisciplary effot that brings together biologists, biomedical engineers and clinicians,” Longaker said. “What we can see in the distance is a transformed medical landscape that is able to seamlessly rejuvenate organs, ultimately extending human lifespan and health span.”