Neurodegenerative diseases like multiple sclerosis (MS) affect millions of people worldwide and occur when parts of the nervous system lose function over time.
Researchers at the University of Maryland School of Medicine (UMSOM) have discovered that a type of skin-related stem cell could be used to help regenerate myelin sheaths, a vital part of the nervous system linked to neurodegenerative disorders.
The discovery into these types of stem cells is significant because they could offer a simpler and less invasive alternative to using embryonic stem cells.
This early-stage research showed that by using these skin-related stem cells, researchers were able to restore myelin sheath formation in mice.
“This research enhances the possibility of identifying human skin stem cells that can be isolated, expanded, and used therapeutically.
In the future, we plan to continue our research in this area by determining whether these cells can enhance functional recovery from neuronal injury,” said Thomas J. Hornyak, MD, PhD, Associate Professor and Chairman of the Department of Dermatology, and Principal Investigator in this research.
“In the future, we plan to continue our research in this area by determining whether these cells can enhance functional recovery from neuronal injury.”
Using a mouse model, Dr. Hornyak’s team of researchers discovered a way to identify a specific version of a cell known as a melanocyte stem cell.
Our bodies are constantly under threat from external hazards.
Skin, the main protection against many such environmental insults, is composed of three layers: the epidermis, dermis, and subcutaneous tissue.
The main specialized cell types of the outermost layer, the epidermis, are the keratinocyte, Langerhans cell, and melanocyte.
To guard against hazardous ultraviolet radiation (UVR) from sunlight, the melanocyte contains a unique organelle, the melanosome, that produces the pigment, melanin, to provide photoprotection.
The melanocyte is an appealing model for studying cellular function and differentiation, because they work as a single-cell unit and have a distinctive differentiation product in the form of melanosomal organelles and melanin.
Interest in melanocytes and skin pigmentation can be traced back many centuries to Asia, where fancy mice were bred for their different coat colors (1).
For many of these mouse strains, it was eventually discovered that the variation in coat color was the result of differences in genes involved in the production of melanin and the function of the melanocytes.
These studies provide a foundation for our yet incomplete understanding of melanocyte function.
Melanocyte stem cells have specific qualities that make them an excellent model for the study of stem cells generally.
First, they can be relatively non-invasively harvested from the skin.
Within the skin, melanocyte stem cells are most likely located within a specific anatomic niche, making them easy to find and isolate; specifically, in murine skin, melanocyte stem cells reside within the bulge region of the hair follicle (2).
A second valuable trait of the melanocyte stem cells is that expansion and differentiation of daughter cells are closely coupled to the hair growth cycle (at least in murine systems).
Quiescence or growth of melanocytes may be easily controlled through hair depilation.
Lastly, dysfunction of this population is easily identified by the resulting defects in pigmentation.
Improper maintenance of melanocyte stem cells, such as through increased apoptosis as a consequence of Bcl2 deficiency, causes stem cell loss and hair graying (3).
Several intrinsic qualities of melanocytes in general are useful for any studies or techniques that require manipulation of these cells.
These traits include the relatively long life of melanocyte stem cells in comparison to other skin populations, such as keratinocytes.
In addition, melanocytes work as a single-cell unit, and growth and differentiation are tightly controlled through signals from surrounding cells.
In addition, melanocytes are derived from the neural crest, a very plastic embryonic tissue.
Due to their developmental origins, melanocyte stem cells’ multipotency and ability to migrate readily to new locations may be innate properties.
The multipotent and highly prolific melanocyte stem cells provide an important stem cell source for regenerative medicine applications.
Such cells could be utilized for gene therapy through ex vivo gene delivery and re-transplantation.
These excellent qualities of the melanocyte stem cell, including its long lifespan, ability to be manipulated in vivo and ex vivo, plasticity regarding its differentiation choices, and capability to migrate in vivo, open the doors to great opportunities for stem cell therapy.
The same traits that make the melanocyte stem cell so promising for stem cell therapeutics may also help explain why melanomas (tumors derived from melanocytes) are often so aggressive and deadly.
Melanoma tends to metastasize early in the disease process and is often fatal.
The incidence of melanoma, unlike that of many other cancer types, has been rising steadily for over half a century (4).
Melanocyte are the precursor cells to the cells in skin and hair follicles that make a pigment known as melanin, which determines the color of skin and hair.
These melanocyte stem cells have the ability to continue to divide without limit, which is a trait that is not shared by other cells in the body.
Additionally, the researchers discovered that these stem cells can make different types of cells depending on the type of signals they receive
This research was published in PLoS Genetics.
Importantly, unlike the embryonic stem cell, which must be harvested from an embryo, melanocyte stem cells can be harvested in a minimally-invasive manner from skin.
Isolating Skin Stem Cells for New Therapies
Dr. Hornyak’s research team found a new way to not only identify the right kind of melanocyte stem cells, but also the potential applications for those suffering from neurodegenerative disorders.
By using a protein marker that is only found on these specialized cells, Dr. Hornyak’s research group was able to isolate this rare population of stem cells from the majority of the cells that make up skin.
Additionally, they found that there exist two different types of melanocyte stem cells, which helped in determining the type of cells they could create.
Using this knowledge, the UMSOM researchers determined that under the right conditions, these melanocyte stem cells could function as cells that produce myelin, the major component of a structure known as the myelin sheath, which protects neurons and is vital to the function of our nervous system.
Some neurodegenerative diseases, like multiple sclerosis, are caused by the loss of these myelin-producing, or glial, cells which ultimately lead to irregular function of the neurons and ultimately a failure of our nervous system to function correctly.
Growing Melanocyte Stem Cells
Dr. Hornyak and members of his laboratory grew melanocyte stem cells with neurons isolated from mice that could not make myelin.
They discovered that these stem cells behaved like a glial cell under these conditions.
These cells ultimately formed a myelin sheath around the neurons that resembled structures of a healthy nerve cell.
When they took this experiment to a larger scale, in the actual mouse, the researchers found that mice treated with these melanocyte stem cells had myelin sheath structures in the brain as opposed to untreated mice who lacked these structures.
Dr. Hornyak and members of his laboratory grew melanocyte stem cells with neurons isolated from mice that could not make myelin. They discovered that these stem cells behaved like a glial cell under these conditions. These cells ultimately formed a myelin sheath around the neurons that resembled structures of a healthy nerve cell. When they took this experiment to a larger scale, in the actual mouse, the researchers found that mice treated with these melanocyte stem cells had myelin sheath structures in the brain as opposed to untreated mice who lacked these structures. Image is credited to Hornyak et al.
“This research holds promise for treating serious neurodegenerative diseases that impact millions of people each year.
Our researchers at the University of Maryland School of Medicine have discovered what could be a critical and non-invasive way to use stem cells as a therapy for these diseases,” said UMSOM Dean, E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor.
Funding: Dr. Hornyak’s research was funded by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, and the U.S. Department of Health & Human Services. the Biomedical Laboratory Research & Development Service, VA Office of Research Development, and U.S. Department of Veterans Affairs.
University of Maryland School of Medicine
Joanne Morrison – University of Maryland School of Medicine
The image is credited to Hornyak et al.
Original Research: Open access
“CD34 defines melanocyte stem cell subpopulations with distinct regenerative properties”. Sandeep S. Joshi, Bishal Tandukar, Li Pan, Jennifer M. Huang, Ferenc Livak, Barbara J. Smith, Theresa Hodges, Anup A. Mahurkar, Thomas J. Hornyak.
PLOS Genetics. doi:10.1371/journal.pgen.1008034