Every single human being on the globe started as a single cell. This cell is called a stem cell and holds the entire cellular blueprint of a person. All the information required to build a person is present in distinct patterns of deoxyribonucleic acid, commonly called DNA. Segments, or pieces of this DNA code are used as a template that builds proteins responsible for providing a cell with an identity that determines its function. For example, pacemaker cells in the heart must be able to signal the heart to pump which is a very different function from stomach cells that secrete acid to aid in food digestion. These cells contain the same information, the same DNA, but different pieces of DNA code are being used to make specific proteins that allow the cell to perform its appropriate function. The ability for a stem cell to turn into any kind of cell, of the same species (of course), provides scientists with the opportunity to study how cells change and then use that knowledge to understand disease progression or possibly build new tissue.
The original use of the term stem cell appeared in 18681 in a paper published by German biologist Ernst Haeckel. He used the German term for stem cell, “stammzelle” to describe a unicellular ancestor from which many-celled organisms evolved from. Although the term stem cell is no longer used in this context, in an 1877 publication, Haeckel also described a “stammzelle” as a fertilized egg that gives rise to all the cells of a single animal. These are now specified as embryonic stem cells and have been the source for ethical concerns within both the scientific and larger global community.
Pioneering work with stem cells was performed by Canadian scientists Drs. James Till & Ernest McCulloch. They stumbled across the self-renewing capabilities of bone marrow cells which we now know is the source of the different types of blood cells2. In their experiments, they exposed mice to radiation to disable their bone marrow from being able to make functional blood cells. After the radiation treatment, they were injected with bone marrow cells from healthy mice. These single-source injected cells produced colonies that contained the three different lineages of blood cell types: 1) erythrocytic which produce red blood cells; 2) granulocytic which produce white blood cells; and 3) megakaryocytic which produce platelets3. These experiments proved that one type of cell, a stem cell, can become many other types of cells. This work was instrumental in developing the earliest, and currently still the most successful, type of stem cell therapy available: the bone marrow transplant. This treatment is used to treat leukemia, where radiation is used to disable the cancerous bone marrow of the patient and then replaced with healthy bone marrow from a donor.
Even though the functional discovery of stem cells occurred in the 60s, it wasn’t until the 80s before scientists identified embryonic stem cells. Embryonic stem cells are the most versatile stem cell because they have the innate ability to turn into all the different cell types required to build an organism. This trait is called pluripotency and is what makes them so attractive to scientists. Imagine being able to build any tissue from scratch! Studying embryonic stem cells is not only useful for building tissue, but also understanding how our individual parts develop and work together to become a functional, conscious being. However, the ethical concerns surrounding work with embryonic stem cells inspired scientists to look for alternative techniques to mimic embryonic stem cell behaviour.
All the information that an embryonic stem cell has is stored in its DNA, so the key is to manipulate the DNA to trick the cell into thinking it is an embryonic stem cell. This astonishing feat was done by Dr. Shinya Yamanaka who developed inducible pluripotent stem cells or iPSCs. He was awarded the Nobel Prize in 2012 for finding four crucial factors that can turn any adult cell into an embryonic-like stem cell4. These factors, coined Yamanaka factors, are transcription factors which bind to specific DNA sequences to control which parts of the DNA should be transcribed into messenger RNA and subsequently form proteins. Transcription factors are naturally present in cells and are crucial in determining which pieces of DNA are needed to be coded for cells to function properly. Dr. Yamanaka was originally studying 24 different factors, but his staff research investigator, Dr. Kazutoshi Takahashi, worked diligently to reduce it down to four factors – Oct 3/4, Sox2, Klf4, and c-Myc5. At the time, this was an astonishing feat because these scientists essentially took an adult skin cell, called a fibroblast, and reprogrammed it, tricking it into thinking it was an embryonic stem cell. This technique takes any cell and essentially programs it to become any other kind of cell! The next step was to ensure that this experiment is reproducible so that researchers all around the world would be able to study pluripotent stem cells without needing access to embryonic stem cells. Now, just over a decade after their discovery, there are over 6000 scientific publications that have used iPSCs.
Access to pluripotent stem cells are important when studying organ development and disease progression; however, there is another category of stem cells that are just as important. They are adult stem cells and everybody has them! Although they can turn in many different cell types, they are limited with the variety of cells they can become and thus are called multipotent. Adult stem cells are present in nearly all the organs and tissues of the body and are responsible for their natural turnover and repair6. As previously mentioned, bone marrow is a source of stem cells. In fact, there are two different types of adult stem cells present in bone marrow: mesenchymal stem cells and hematopoietic stem cells. Mesenchymal stem cells maintain one’s fat, bone, and cartilage tissue whereas hematopoietic stem cells are the source for the many different blood cell types. Adult stem cells in the brain are responsible for memory and both hair and skin cells come from the same stem cell source.
The fascinating discovery of stem cells has propelled the biomedical field forward. It allows scientists to study and better understand how our body grows, functions, and heals itself. This knowledge is important when figuring out how diseases develop and progress. Currently, scientists and engineers are working together using both stem cells and 3D printing, to build healthy new tissues using the patient’s own tissue as the source of cells. Hopefully one day, scientists and physicians will be able to replace diseased tissue with healthy lab grown tissue. For now, much of this research is still in early developmental stages and requires funding and support to keep progressing forward safely.
Ingenious scientists and engineers from many different fields working together to improve 3D printing for tissue engineering. The next frontier for 3D printing in the tissue engineering field would be to print using living cells to custom-made functional organs. Science isn’t there yet, so if you haven’t already, please consider being a organ donor in your area, because it is the only option available now for those in need. Hopefully one day, it won’t be.