Where do adult stem cells come from?
Adult stem cells receive much interest in the scientific community thanks to their ability to self-renew and generate numerous types of cells and tissues. There are two categories of stem cells: embryonic and adult.
Unlike embryonic stem cells, which have the ability to differentiate into more than one cell type, most adult stem cells are capable of forming only the types of tissue from which they originated. However, due to the controversy surrounding embryonic stem cell use, more and more researchers have turned their attention to the study of adult stem cells.
As a result, we now know of several adult tissues that serve as sources for stem cells. This is great news for people who suffer from degenerative conditions like osteoarthritis, muscular dystrophy and even Alzheimer’s disease.
The list of adult tissues known to contain stem cells keeps growing, and it includes bone marrow, brain tissue, peripheral blood and blood vessel tissue, skeletal muscle tissue, and liver and pancreas tissue.
Adult stem cells can be obtained from multiple tissues
Neural brain cells (NSCs) are multipotent cells that generate the central nervous system. They undergo asymmetric cell division, resulting in one non-specialized (blank) cell and one specialized cell. Japanese researchers have been able to use NSCs to replace dying neurons in lab mice . Currently there are numerous ongoing investigations into the response of NSCs in multiple sclerosis (MS) and Parkinson’s disease patients. The results may have future applications in the treatment of additional neurological conditions.
Hematopoietic stem cells (HSCs) are stem cells harvested from blood or bone marrow. They can differentiate into variety of specialized cells, such as white blood cells, which fight infection, and red blood cells, which carry hydrogen and platelets, and are responsible for blood clotting.
The downside of HSC stem cells is that their ratio in bone marrow is very low—1 in every 10,000-15,000 cells, which slows down the harvesting process considerably. Bone marrow also hosts skeletal stem cells (STCs), which give rise to osteoblasts (bone cells), cartilage and hematopoietic stroma.
An interesting niche of stem cells is found in the surface lining of the small and large intestines (ISCs). These stem cells divide continuously throughout life and are believed to be the source of most forms of cancer of the small intestine and colon. The longevity and renewal rates of ISCs becomes problematic in colorectal cancer, because they promote regeneration of the tumor after therapy.
In healthy adults, the liver is responsible for maintaining the balance between cell gain and cell loss. The liver’s impressive regenerative functions are attributed to hepatocytes, which are believed to be the adult stem cells of the liver. When the liver tears apart from virus infections, inflammation or is sectioned through hepatectomy, hepatocytes activate a stem cell-like behavior, giving rise to new tissue, replacing the lost liver cells.
Another important discovery has been made by Dr. Lola Reid of the University of North Carolina, an accredited expert in the research of liver development . As it turns out, the biliary tree, a network of vessels that connect the liver and pancreas to the intestine, generates a special type of adult stem cells, their major characteristic being pancreatic precursor cells, meaning they are destined to differentiate as pancreatic cells.
In a series of lab tests, these biliary cells have been manipulated to become islets, structures responsible for the production of insulin and c-peptide, a key component in the natural production of insulin. As a result, the blood sugar control in has been found to increased dramatically in lab mice. Dr. Reid hopes that her team’s efforts will speed up the process of finding a cure for diabetes.
Over the past few decades, scientific research has provided us with great insight on adult stem cells and their applications in regenerative medicine.
Unlike embryonic stem cells, adult stem cells can be isolated from a variety of adult tissue, including the brain, bone marrow, peripheral blood and even tumor-derived tissue cells, allowing scientists to avoid the ethical dilemma of using embryonic stem cells entirely. The risk of rejection with adult stem cells is considerably lower (the donor is usually the patient himself), and the differentiation rates are higher, providing much hope for future research to find cures for degenerative conditions in humans.
REFERENCES: MacKlis, Jeffrey D.; Magavi, Sanjay S.; Leavitt, Blair R. (2000). “Induction of neurogenesis in the neocortex of adult mice”. Nature 405 (6789): 951–5
 Biliary Tree Stem Cells, Precursors to Pancreatic Committed Progenitors: Evidence for Possible Life-long Pancreatic Organogenesis – http://www.diabetesresearch.org/file/research-publications/2013-Stem-Cells_Biliary-Tree-Stem-Cells-to-Islets.pdf
Healing damaged lungs with stem cells.
A New study published by scientists from the Weizmann Institute of Science suggests that stem cells may be used for repairing damaged lung tissue. This discovery gives new hope for treating conditions like bronchitis, asthma, cystic fibrosis or emphysema, which affect more than 35 million Americans and are the second leading cause of death worldwide.
Bone Marrow stem cells able to generate new lung tissue
The treatment method proposed by scientists at the Weizmann Institute is based on the similarities between stem cells that reside in the lungs and those in bone marrow. Bone marrow stem cells, when transplanted to a patient, manage to find their way through the blood and to navigate to the designated area where they differentiate.
Acknowledging the similarities between lung and bone marrow stem cells, Professor Yair Reisner of the Immunology Department of the Weizmann Institute tested the ability of lung stem cells to travel to a specific region after transplantation in mice . Before introducing the bone marrow stem cells into mouse models with lung damage, the group of scientists cleared the lungs’ stem cell compartments to clear a path for the transplanted cells.
The injected stem cells managed to reach the empty lung compartments and settle in the lungs, where they differentiated into normal lung tissue,six weeks after transplantation. Results showed that new lung cells continued to be created from the transplanted stem cells 16 weeks after the implantation, ultimately healing the damaged lungs and improving their breathing ability.
The Weizman scientists intend to continue their research by exploring this option further, and possibly create a bank of lung stem cells that can provide cells ready to be transplanted to patients with severe respiratory diseases.
Lung-specific induced pluripotent stem cells (iPSCs)— potential alternative to bone marrow stem cells
This was not the first attempt to heal damaged lungs with stem cell transplants. In a previous study, scientists from the Boston University Medical Center managed to generate 100 new lines of lung-disease specific iPSC from patients with emphysema, cystic fibrosis and other similar conditions. Results suggest that the new stem cell lines could be used for transplantation in patients suffering from lung diseases, thanks to their ability to differentiate to endoderm cells that give rise to lung tissue.
Darrell Kotton, the study’s lead author, highlighted the fact that iPSCs are easier to cultivate in lab conditions than bone marrow stem cells, and are genetically identical to the patient’s cells, so the risk of rejection in such transplants is eliminated. The lung-specific iPSCs obtained by manipulating adult stem cells into a primitive stem cell state could solve some of the hurdles impacting other kinds of stem cell research.
In this study, scientists used skin stem cells manipulated into primitive pluripotent stem cells, with results showing that the iPSCs have the ability to multiply and differentiate into endoderm tissue–the natural precursor of lung cells .
- Chava Rosen, Elias Shezen, Anna Aronovich, Yael Zlotnikov Klionsky et al. – Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice, Nature Medicine, 2015, http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3889.html
- Aba Somers, Jyh-Chang Jean, Cesar A. Sommer, Amel Omari et al. – Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette, Stem Cells, 2010, 28 (10):1728, http://onlinelibrary.wiley.com/doi/10.1002/stem.495/full
The Language of Stem Cell Medicine: What are They? What Makes Them so Special? And What do all Those Acronyms Mean?
Stem cell medicine is based on the concept that physicians can harness the body’s own reserves to heal itself, rather than relying exclusively on drugs or invasive surgical procedures. Stem cell medicine works by deals engineering human stem cells to replace or restore damaged or diseased organs or tissue, or establish normal function in them. While regenerative medicine primarily includes therapies a that utilize stem cells, the term is also used to describe therapies that use progenitor cells, used for many decades in the form of bone marrow transplants, as well as other cellular products such as platelet-rich plasma (PRP).
While both PRP and progenitor cells are widely used in clinical settings, stem cell therapies are still playing catch-up. PRP is used to treat orthopedic injuries and degenerative joint disease.
However, stem cells are in high demand worldwide. The burgeoning field of stem cell medicine is widely understood in a vague sort of way, but few people are aware that there are different kinds of stem cells. They can be derived from different tissue sources, harvested from the patient’s own body or donated. To help establish a better understanding of the stem cell landscape, we’ll start with some basic concepts.
Autologous vs. Allogenic Stem Cells
Stem cell treatments are generally divided into two classes:
- Autologous stem cells – collected from your own body, exclusively for your own use
- allogeneic stem cells, harvested from another person (donor)
Current clinical trials involving both autologous and allogeneic therapies are taking place all over the world. These trials target a wide range of diseases and conditions, from heart disease to orthopedic conditions, to wound healing.
Autologous treatments using your own stem cells can be performed in the same operative session, which eliminates concerns over your body rejecting donor cells. Your stem cells are extracted from your tissue, and reinjected back into your body targeting the area or organ that needs mending. This is a one-to-one therapy.
Allogeneic therapies use stem cells donated from another person. Before these cells can be put into a different human body than the one they came from, they must undergo extensive testing for diseases, and the cells are usually culture expanded in laboratories to achieve higher cell counts. Allogeneic therapies are performed under strict FDA guidelines, as these stem cells can eventually scale up in mass production, be stored and potentially distributed to millions of patients.
Stem Cell Types
Adult stem cells (non-embryonic) are undifferentiated cells found throughout the body that multiply by cell division to replenish dying cells and regenerate damaged tissues.
Stem cells are acquired from various tissue sources, and each tissue source has different potentials for the cells to differentiate. The following information explains these tissue sources and corresponding type of stem cells:
Adult Stem Cells (ASC’s)
In recent decades researchers discovered that stem cells can be found in all adult tissues. These are called adult stem cells, and although they cannot differentiate into every type of cell like embryonic stem cells, they can differentiate into bone, cartilage and adipose (fat) tissue readily. The two most familiar sources of adult stem cells are bone marrow and adipose tissue. More than 2,000 clinical trials have been conducted worldwide using the various tissue sources of adult stem cells.
IPS Cells (induced pluripotent cells)
IPS cells come from adult cells. Their genetic code is biologically manipulated to become pluripotent, which means they can differentiate, or become any other type of cell. Because the genetic code of IPS cells has been altered, they carry a higher risk profile than both adult stem cells and embryonic stem cells.
Embryonic Stem Cells (ES)
Embryonic stem cells, first isolated in mouse embryos in 1981, are derived from the embryo of a human fetus. Controversy has pursued embryonic stem cell research since its inception, over of ethical and religious perceptions. Embryonic stem cells are currently used mainly for research and understanding how regenerative cells work.
Types of Adult Stem Cells
Adult stem cells can be isolated from bone marrow, adipose tissue, umbilical cord blood, peripheral blood, dental pump, and other sources. Most recently, a large number of clinical trials are focusing on stem cells derived from bone marrow and adipose tissue.
Bone Marrow Stem Cells
Bone marrow stem cells were the first recognized form of adult stem cells in the body. Researchers found they could be used to help heal bone and to replace different cell types in the blood. They could also be used in cancer patients whose bone marrow was destroyed by radiation therapy or chemotherapy. Use of bone marrow stem cells is FDA approved under certain conditions.
The drawback with bone marrow stem cells is that they are difficult to extract and not abundant. In order to be used as a treatment, bone marrow stem cells must be expanded in culture in a lab. The FDA places this therapy in the category of a drug, and requires rigorous oversight and testing.
Adipose Derived Stem Cells
In 2001, researchers and plastic surgeons from the University of Pittsburgh discovered that human fat tissue is a very rich source of mesenchymal stem cells (MSCs), multipotent stromal cells that can differentiate into a variety of cell types, and the findings were published in Tissue Engineering Journal. Upon publication, this discovery stirred quite an epiphany in the medical and scientific community—until then, adult MSCs were predominantly believed to be strictly a bone marrow product.
Adipose stem cells (pictured) harvested from body fat. (Photo: Genetic Engineering & Biotechnology News).
The discovery of abundant stem cell populations in body fat tissue changed everything the medical community thought it knew about stem cells overnight. Now, adipose stem cell therapies are driving the plastic and cosmetic surgery industries, and demand among patients keeps rising.
In 2001, researchers and plastic surgeons from the University of Pittsburgh discovered that human fat tissue is a very rich source of mesenchymal stem cells (MSCs), multipotent stromal cells that can differentiate into a variety of cell types. When their findings were published in Tissue Engineering Journal, the discovery stirred quite an epiphany in the medical and scientific community—until then, adult MSCs were predominantly believed to be strictly a bone marrow product.
Little did those researchers realize at the time that their discovery would revolutionize cosmetic surgery in less than a decade.
Adipose tissue offers distinct advantages over bone marrow tissue. Adipose fat is easier to extract than bone marrow, and the stem cell population contained in fat tissue is far more abundant than in bone marrow. One ounce of fat contains 300-500 times as many mesenchymal stem cells as an ounce of bone marrow. And unlike bone marrow, because of autologous adipose tissue’s copious stem cell count, most procedures using them do not require cells to be expanded in a lab, which means that most adipose stem cell therapies can be performed in the same operative procedure. Because bone marrow typically needs to be culture expanded for days in a lab before they can be re-injected back into a patient and adipose cells do not, there are plenty of advantages to adipose stem cell therapies.
Over the past 10 years, plastic surgeons have established safe and convenient ways to remove fat and isolate the stem cells for use in cosmetic procedures. And since adipose stem cells are extracted and reintroduced to the patient’s own body, the risk of rejection that goes with donor stem cells is eliminated. Scores of ongoing clinical trials using adipose stem cells have already proven their safety and efficacy in a variety of applications. Anti-aging therapies using adipose stem cells, for instance, have grown exponentially in popularity.
As we age, cells become progressively damaged over time from sun, toxins in the environment, and the natural loss of moisture that keeps youthful skin full and wrinkle-free. Adipose stem cells work to regenerate and repair that damaged tissue, and adjunctive treatments can potentially slow down or reverse the aging process. Those cells possess a unique anti-aging effect by means of regenerating and repairing organs—including skin—damaged by environmental elements we are exposed to in our daily life, and by improving immune functions.
This discovery has created an international demand for stem cell anti-aging therapies, which since these procedures are non-invasive (no surgery involved), make for a faster recovery and significantly less downtime for patients. Many patients and physicians feel that adipose stem cells also create a more natural appearance for recipients than traditional cosmetic surgery procedures. Some cosmetic stem cell physicians have taken it up a notch with cell assisted fat transfer, in which autologous adipose-derived (stromal) stem cells are used in combination with lipoinjection for even softer, more natural results.
Here’s how it works: a stromal vascular fraction (SVF) containing ASCs is freshly isolated from half of the aspirated fat and recombined with the other half. This process converts relatively ASC-poor aspirated fat to ASC-rich fat, reducing the potential for postoperative atrophy of injected fat to a minimal level, which clinical trials have found does not change substantially after two months.
Adipose Tissue as a Regenerative Therapy
While adipose tissue is a definitive source of stem cells, what if you don’t need to isolate or separate the stem cells to benefit from their regenerative powers?
Plastic surgeons have known for years that fat grafting itself, without extracting the stem cells, has regenerative properties. Cosmetic surgeons have developed safe and predictable techniques for fat grafting and have documented the regenerative effects of fat grafting in different tissues, for a variety of conditions and diseases. Adipose stem cell rich fat grafting has been documented to reverse radiation tissue damage, something that was considered irreversible until recently. Current clinical studies are documenting the regenerative effects of fat grafting in areas no one suspected, such as autoimmune diseases and degenerative joint disease. Unlike bone marrow tissue, adipose tissue is easy to extract, it’s abundant, and it’s effective in ways researchers have only begun to discover. Cell-assisted fat grafting serves a valuable role helping people with disfiguring injuries and birth defects. Plastic surgeons
Plastic surgeons have acquired decades of experience in harvesting and refining adipose tissue for treating patients. Thanks to the remarkable level of expertise they have developed with adipose tissue, experts now play a leading role in developing its evolving regenerative applications. Regenerative medicine is changing the landscape of cosmetic and reconstructive surgery, and aesthetic medicine—and it keeps getting better!
Chuck Dandridge, a Mansfield, Texas resident, became the first adult in the U.S. to receive a newly modified stem cell transplant that uses genetically engineered blood cells from a family member. The milestone was announced by researchers at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center in Dallas, where the procedure was performed.
Dandridge’s medical journey began in 2013, with a routine doctor’s visit to check his cholesterol levels; lab tests revealed low blood counts and further testing confirmed Dandridge’s diagnosis of myelodysplastic syndrome, also called pre-leukemia or MDS. By 2014, the leukemia had progressed to acute myeloid leukemia (AML), which, according to the National Cancer Institute, affects more than 20,000 Americans annually.
Dandridge was referred to UT Southwestern’s Simmons Cancer Center, where his leukemia was tested for genetic mutations.
“We wanted to know whether he had specific mutations in his cancer cells,” says
Madhuri Vusirikala, M.D., Professor of Internal Medicine and the primary investigator of many UT Southwestern clinical trials related to bone marrow transplantation.
“We found a mutation called IDH 2, which causes the body to produce an abnormal protein that promotes excessive cell growth. If you can target that mutation and stop the abnormal protein from being produced, then cells start behaving normally.”
Dandridge enrolled in a UT Southwestern clinical trial for a therapy called AG-221. He took four pills each morning for the next eight months. During that time, Dandridge saw marked improvement although he did not go into complete remission, according to Vusirikala.
That success made him eligible for a potentially curative stem cell transplant. But finding a donor proved challenging.
“The best chance of finding a full match is usually a full sibling; however, Chuck has no full siblings,” Vusirikala says. Additionally, Dandridge is African American, and minorities are under-represented in the National Marrow Donor Registry—about 70 percent of registry donors are Caucasian. The search for an unrelated donor was unsuccessful.
Vusirikala says that he knew Dandridge’s daughter and his son would be at least a half match. Since using a same-sex donor is preferred, as it reduces the risk of complications, his son Jon, 31, emerged as the best choice. But the risk of graft-versus-host-disease (GvHD) following a transplant using a half-match is very high, so they needed a better way to deal with the GvHD risk.
Once again, Mr. Dandridge volunteered for a cutting-edge clinical trial, known as BP-001, which processed the stem cells used in the transplant to reduce the risk of rejection and engineered blood cells that can be targeted if GvHD develops after the transplant.
The processes being tested in BP-001 are in clinical development by Houston-based Bellicum Pharmaceuticals. The study is evaluating patients with blood cell cancers who have a peripheral blood stem cell transplant from a partially matched relative. Immune cells (T cells) from the related donor are separated from the rest of the stem cells and genetically engineered in the Bellicum laboratory, and then given to the patient along with the stem cell transplant.
These engineered T cells are modified to include a suicide gene with the help of a retrovirus. If the patient develops GvHD after transplant, the side-effect can be treated by giving a drug called rimiducid to activate the suicide gene and cause the activated GvHD-causing cells to be eliminated. The stem cells given for the transplant were also processed prior to giving them back to Dandridge to reduce the risk of graft rejection as well as GvHD.
The genetically engineered blood cells were transplanted from Dandrige’s son, Jon, 31, to the father in three, two-hour infusions at William P. Clements Jr. University Hospital in July, 2015, and today the elder Mr. Dandridge’s leukemia is in remission. His immune system is recovering, and the former Norman, Oklahoma YMCA CEO is now mentoring first-time CEOs for the YMCA.
A new discovery by researchers on how to activate lab-grown beta cells to mature into functioning cells that produce and release insulin in response to glucose take a significant step toward a cell therapy treatment for diabetes.
Difficulties in manipulating beta cells derived from human stem cells to mature beyond the precursor stage into fully functioning insulin releasers has been an on-going challenge for researchers..
However, researchers from the Salk Institute for Biological Studies and a team of researchers have achieved this goal with lab-grown beta cells by activating a protein called estrogen-related receptor γ (ERRγ). Their study findings were recently published in the journal Cell Metabolism.
Self-renewing capacity of human pluripotent stem cells (hPSCs)
Ronald Evans, senior author of the study, titled, “ERRγ Is required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells,” says the self-renewing capacity of human pluripotent stem cells (hPSCs) and their ability to differentiate into most cell types—from neurons to skin cells, to muscles cells and insulin-producing pancreatic beta cells—has inspired many research teams to find ways to make glucose-responsive beta cells in the lab.
Evans and his research team discovered the answer to the insulin-releasing cell conundrum, and summed it up thusly:
“In a dish, with this one switch, it’s possible to produce a functional human beta cell that’s responding almost as well as the natural thing.”
Evans, a molecular biologist at the Salk Institute, says that to create the different types of cells in the lab, researchers coax the pluripotent stem cells (hPSCs) down the various branching paths that fetal cells normally travel in order to differentiate into the various cell types. However, he explains there are many developmental points in this process, and in the case of lab-grown pancreatic beta cells, research kept getting stuck at an early stage.
Adult beta cells have more ERRγ protein for a very energy-intensive process
In order to determine what might trigger the next step in getting the cells to mature, the researchers compared transcriptomes of adult and fetal beta cells. The transcriptome contains, among other things, the full catalog of molecules that switch genes on and off in the genome, which led them to discover that the nuclear receptor protein ERRγ was more abundant in adult beta cells. The team was already familiar with the protein’s role in muscle cells and had studied its ability to enhance endurance running.
Evans says that in muscles, protein promotes greater growth of mitochondria—the power generators inside cells that accelerate the burning of sugars and fats to make energy.
“It was a little bit of a surprise to see that beta cells produce a high level of this regulator,” Evans says. “But beta cells have to release massive amounts of insulin quickly to control sugar levels. It’s a very energy-intensive process.”
The research team then decided to run some tests to look more closely at what role ERRγ might play in insulin-producing beta cells.
A new era in creating functional, insulin-producing beta cells
After they genetically engineering a deficiency of ERRy in mice, the researchers found the animals’ beta cells did not produce insulin in response to spikes in blood sugar.
Next they tried to get beta cells made from hPSCs to produce more ERRγ, and it worked! The cells in culture began to respond to glucose and release insulin.
Finally, the team transplanted the lab-grown insulin-producing beta cells into diabetic mice and found that from day one, the cells produced insulin in response to glucose spikes in the animals’ blood.
Evans and the research team were justifiably excited by the results. It appears that just switching on the ERRγ protein is sufficient to get the lab-grown beta cells to mature and produce insulin in response to glucose – both in cultures and in live animals.
Speculating on the implications of their findings, Evans suggests that when a fetus is developing, because it gets a steady supply of glucose from the mother, it does not need to produce insulin to regulate its blood sugar, so the switch is inactive. But, when the baby is born and takes its first breath and takes in oxygen, this activates the switch.
Previous lab attempts to produce beta cells got stuck at the fetal stage. The Salk Institute researchers discovered how to take it to the adult stage, using the same protein that is switched on in nature.
“I believe this work transitions us to a new era in creating functional beta cells at will,” Evans says.
He and his research team now plan to examine how the switch might work in more complex models of diabetes treatments.
The Salk Institute study proceeds another study Medical News Today in which researchers generated mini-stomachs that produce insulin when transplanted into mice.
Scientists have been studying stem cells for decades, and many of their findings, all pretty remarkable, aren’t widely circulated. Periodically, we will share one of these stem cell research breakthroughs here on this blog.
Summary: The skin renews, heals wounds, and regenerates the hair that covers it thanks to a small group of stem cells. These cells continually produce new ones, which appear on the skin surface after a few days. A 2008, released online July 28, 2016, has identified two proteins that are fundamental to conserve skin stem cells, and shows that without these proteins these cells are lost. Researchers find that these proteins, Dnmt3a and Dnmt3b, are altered similarly to tumor cells found in leukemia, lung cancer and colon cancer, which may help researchers discover if the proteins contribute to tumor development.
Amazing stem cell breakthroughs
The first amazing stem cell research breakthrough you may never heard of is a 2008 study, published online July28, 2016 in the journal “Cell Stem Cell,” titled “Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis,” led by Catalan Institution for Research and Advanced Studies (CREA) researcher Salvador Aznar Benitah, initiated at the Institute for Research in Biomedicine (IRB Barcelona).
Researchers identify two proteins— Dnmt3a and Dnmt3b—fundamental to conserving skin stem cells.
The study examines the continuous regeneration of the skin and hair that covers it, thanks to a small group of stem cells. Study researchers identified two proteins— Dnmt3a and Dnmt3b—that are fundamental to conserving skin stem cells. “Without these proteins, skin stem cells are not activated and the stem cells collapse and disappear from the tissue,” according Benitah, head of the Stem Cells and Cancer lab at IRB Barcelona.
Lorenzo Rinaldi, a la Caixa PhD student and first author of the study, identified all the regions of the genome that harbors these proteins. Rinaldi has observed that these two proteins exert their activity on gene enhancers and super-enhancers. Researchers were surprised to see that the two proteins, which had previously been associated with gene repression through DNA methylation, are activated in the most transcriptionally active regions of stem cells.
Researchers observe Dnmt3a and Dnmt3b at the genomic level for the first time
“We had never observed this activity because we were unable to study the global distribution of Dnmt3a and Dnmt3b at the genomic level,” Rinaldi says. “Thanks to advances in sequencing techniques, more researchers are observing the very mechanism that we have described.”
Of the 12,000 gene enhancers in the genome, about 300 are super-enhancers related to stem cells. The two proteins exert their function in these regions in order to trigger the approx. 1,000 genes required for the self-renewing capacity of skin stem cells. By methylating the super-enhancer, these proteins trigger the first step of the machinery that leads to the amplified expression of these essential genes for the stem cell.
Link to cancer
Among the various features related to tumor cells are three components:
• these cells show altered DNA methylation.
• gene enhancers, in addition to the bodies of the genes themselves, are highly mutated. These observations have been made possible thanks to mass sequencing of tumor cell genomes.
• these two proteins, Dnmt3a and Dnmt3b, are altered in many types of tumors, such as those encountered in leukemia, lung cancer and colon cancer.
Each of these three components is associated with the development of various kinds of cancer. Given that these proteins activate gene expression enhancers through DNA methylation, researchers believe that further studies of them in cancer cells would be helpful in determining whether they participate in tumor development.
The study was funded by the Spanish Ministry of Economy and Competitiveness and ERDFs. Benitah’s lab is also supported by The European Council for Research (ERC), the Worldwide Cancer Research Foundation, the Fundació Marató de TV3, the Fundación Vencer el Cáncer, the Fundación Botín and the Government of Catalonia.