Stem cell basics and applications.
When a scientist is asked to describe stem cells, words that come to mind include: pluripotent, self-renewal, and regeneration. Embryonic stem cells harbor all three of these traits. They are derived from early stage embryos and are capable of differentiating into any type of cell in the human body (this is what scientists refer to as “pluripotency”). Researchers are able to grow them in culture dishes for long periods of time because of their ability to divide and produce more copies of themselves (also known as the ability to “self-renew”). They are valuable tools and many labs use embryonic stem cells to model and understand human development and various human diseases.
Stem cells are also well known for their ability to regenerate tissues. Humans aren’t lizards, and they can’t regrow entire body parts or organs (with the exception of the amazing regenerative capacity of the human liver). However, adult stem cells present in specific tissues, such as the bone marrow (hematopoietic stem cells), brain (neural stem cells), and heart (cardiac stem cells), play very important roles in maintaining tissue homeostasis and function by replacing the existing cells that die off over time. Adult stem cells are a more mature version of embryonic stem cells, meaning that the differentiated cell types they produce are specific to the tissue that the stem cells inhabit.
In cases of injury or disease, adult stem cells in affected tissues can divide and differentiate to repopulate certain cell types and repair or restore function. Thus, scientists and clinicians have turned to adult stem cells as promising candidates for regenerative applications to treat diseases of aging and traumatic injury. Bone marrow transplants, which contain hematopoietic stem cells, are a classic example. Doctors use healthy bone marrow to reconstitute a sick patient’s immune system and to treat patients with blood cancers and other genetic or immune disorders. More recently, transplants of other adult stem cell types are being explored as potential treatments for traumatic conditions such as spinal cord injury.
When stem cells get old…
But what happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. As mentioned previously, adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.
Let’s take a closer look at a few of the culprits that make stem cells grow old.
- DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky.
- Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease.
- Mitochondrial dysfunction. Mitochondria are the batteries that power our cells (think of the energizer bunny: mitochondria keeps our cells going and going…). Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.
Of course there are many other factors that cause adult stem cell aging (see scientific figure below), but for the sake of not getting to technical, we will leave these other causes for future blog posts.
Can we rejuvenate aging stem cells?
So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue.
However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.
One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.
Final words on stem cell aging and human health.
Aging stem cells and their impact on aging-related diseases and injury repair are issues that still need to be addressed. In general though, scientists and the general public view stem cells as a promising therapeutic option for treating or curing patients with unmet medical needs. Clinical trials using human stem cell transplantations are already underway for the treatment of spinal cord injury and age-related macular degeneration.
While everyone is eagerly waiting to see the results of these clinical trials, in the mean time, scientists should remember that they can use the tools that already exist in the human body. If we find a way to reset the clock on aging adult stem cells in humans, we will have a new and powerful strategy for preventing disease, repairing tissue damage, and prolonging lifespan.
For more information on stem cell aging and rejuvenation, check out these reviews:
- Aging and stem cell renewal (StemBook)
- Stem cell aging: mechanisms, regulators and therapeutic opportunities (Nature Medicine)
- Manifestations and mechanisms of aging (Journal of Cell Biology)
- Aging-induced stem cell mutations as drivers for disease and cancer (Cell Stem Cell)
Stem Cell Clinical Trials