Buck Institute scientists say impaired interactions between macrophages and stem cells are likely players in human intestinal maladies like IBS, leaky gut and colorectal cancers
May 25, 2015/NOVATO, CA: Having a healthy gut may well depend on maintaining a complex signaling dance between immune cells and the stem cells that line the intestine. Scientists at the Buck Institute are now reporting significant new insight into how these complex interactions control intestinal regeneration after a bacterial infection. It’s a dance that ensures repair after a challenge, but that also goes awry in aging fruit flies — the work thus offers important new clues into the potential causes of age-related human maladies, such as irritable bowel syndrome, leaky gut and colorectal cancer.
“We’ve dissected a very complex signaling interaction,” said senior scientist and Buck faculty Heinrich Jasper, PhD. “By doing so temporally we’ve clearly established a role for the immune system both in initiating the regenerative process and in shutting it down – activities that are essential for maintaining tissue homeostasis.”
Publishing in the May 25, advance online edition of Nature Cell Biology, researchers in the Jasper lab show that the macrophage-like hemocytes (which comprise the cellular immune system in flies) go to the intestines ofDrosophila following damage. The hemocytes secrete the growth factor Dpp (a homologue of BMP, which has many functions, including the control of mobility, differentiation and invasiveness of normal cells), setting off the regenerative process by activating specific receptors in stem cells. In a fascinating twist, stem cells switch their response to Dpp in the middle of the regenerative response by turning on other Dpp-related receptors, which in turn instruct the stem cells to go back to a quiescent or quiet state. Jasper says it’s a balancing act that both allows for healing and prevents excessive cell proliferation, which could lead to pre-cancerous dysplasia. “The temporal sequence of cell interactions during injury-induced regeneration is only beginning to be understood,” said Jasper. “The proper timing of these interactions may be key in maintaining a healthy gut.”
Jasper says aging makes it harder for the stem cells to switch gears between proliferation and quiescence and that flies suffer from age-related intestinal dysfunctions similar to those experienced by humans.
In these images, the ability of the new Cas9 approach to differentiate stem cells into brain neuron cells is visible. On the left, a previous attempt to direct stem cells to develop into neuronal cells shows a low level of success, with limited red–colored areas indicating low growth of neuron cells. On the right, the new Cas9 approach shows a 40–fold increase in the number of neuronal cells developed, visible as red-colored areas on the image. Credit: Wyss Institute at Harvard University
New mechanism for engineering genetic traits governed by multiple genes paves the way for various advances in genomics and regenerative medicine
When it comes to gene expression – the process by which our DNA provides the recipe used to direct the synthesis of proteins and other molecules that we need for development and survival – scientists have so far studied one single gene at a time. Anew approach developed by Harvard geneticist George Church, Ph.D., can help uncover how tandem gene circuits dictate life processes, such as the healthy development of tissue or the triggering of a particular disease, and can also be used for directing precision stem cell differentiation for regenerative medicine and growing organ transplants.
The findings, reported by Church and his team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School in Nature Methods, show promise that precision gene therapies could be developed to prevent and treat disease on a highly customizable, personalized level, which is crucial given the fact that diseases develop among diverse pathways among genetically–varied individuals. Wyss Core Faculty member Jim Collins, Ph.D. was also a co-author on the paper. Collins is also the Henri Termeer Professor of Medical Engineering & Science and Professor in the Department of Biological Engineering at the Massachusetts Institute of Technology.
Biologists have shown in rats that chronic stress makes stem cells in the brain produce more myelin-producing cells and fewer neurons, possibly affecting the speed of connections between cells as well as memory and learning. This could explain why stress leads to mental illness, such as PTSD, anxiety and mood disorders, later in life.…
Does stress affect brain connectivity?
Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala — the seat of the brain’s fight or flight response — and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.
“You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.”
Stress tweaks stem cells
Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells.
The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said.
Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones.
This news release is available in German.
IMAGE: A biopsy punch arranges the biopolymer substrate into the appropriate shape (left). Cells then colonize these circular discs in cell culture vessels (right).
It all began with the pancreas. Prof. Charli Kruse, head of the Fraunhofer Research Institution for Marine Biotechnology EMB in Lübeck, still remembers it well. The researchers had isolated some cells taken from the organ in a petri dish as part of their research – their aim was to investigate the function of the protein Vigilin, which is produced in the gland cells. “Suddenly we realized that these cells were reproducing in an unusual way, since the microscope showed not only gland cells in the dish but nerve and muscle cells, too.” Stem cells had formed out of the gland tissue and multiplied to form a variety of different cells. It quickly became apparent that other gland cells shared the same capability: “We slowly worked our way outward from the internal organs until we got to the skin – and the sweat glands. Again, this yielded the same result: a petri dish full of stem cells.” Up to now the sweat glands haven’t really received much attention since laboratory animals such as mice or rats have them only on their paws. A human being, on the other hand, possesses up to three million – predominantly on the soles of the feet, palms of the hand, armpits and forehead.
Healing stem cells obtained from the armpit
Biologists and medics use stem cells to obtain new tissue to replace cells that are damaged or diseased. They play a particularly important role in healing wounds. Stem cells taken from the patient’s own body are ideal because there is no chance of the body rejecting them. Getting at them, however, requires a cumbersome operation to extract the stem cells either from bone marrow or from the blood. “The sweat glands are significantly easier to get to. All that is required is a short walk-in walk-out visit to your dermatologist. We can obtain stem cells from less than 3 millimeters of underarm skin,” explains Kruse. When grafted to a skin injury, these stem cells can have a very beneficial effect on the healing process. Whether it is the cells themselves that build new skin cells and blood vessels or whether their role is to manage healing processes by releasing growth hormones that in turn activate immune cells is currently undergoing investigation.
Tests conducted by the scientists on animals and on human skin in the petri dish have demonstrated the beneficial effect of stem cells in healing injuries.
From the 6 January 2012 US Food and Drug Administration (FDA)
Stem cell therapies offer the potential to treat diseases or conditions for which few treatments exist.
Stem cells, sometimes called the body’s “master cells,” are the precursor cells that develop into blood, brain, bones and all of your organs. Their promise in medical treatments is that they have the potential to repair, restore, replace and regenerate cells that could then be used to treat many medical conditions and diseases.
But the Food and Drug Administration (FDA) is concerned that the hope that patients have for cures not yet available may leave them vulnerable to unscrupulous providers of stem cell treatments that are illegal and potentially harmful.
FDA cautions consumers to make sure that any stem cell treatment they are considering has been approved by FDA or is being studied under a clinical investigation that has been submitted to and allowed to proceed by FDA.
FDA has approved only one stem cell product [Flahiff’s emphasis], Hemacord, a cord blood-derived product manufactured by the New York Blood Center and used for specified indications in patients with disorders affecting the body’s blood-forming system.
Regulation of Stem Cells
FDA regulates stem cells in the U.S. to ensure that they are safe and effective for their intended use.
“Stem cells can come from many different sources and under the right conditions can give rise to many different cell types,” says Stephanie Simek, Ph.D., deputy director of FDA’s Office of Cellular, Tissue and Gene Therapies.
Stem cells that come from bone marrow or blood are routinely used in transplant procedures to treat patients with cancer and other disorders of the blood and immune system.
Umbilical cord blood is collected from a placenta with the birth mother’s consent. Cord blood cells are then isolated, processed, and frozen and stored in a cord blood bank for future use. Cord blood is regulated by FDA and cord blood banks must follow regulatory requirements.
But there are many other stem cell products, including other cord blood-derived products, that have been reviewed by FDA for use in investigational studies, says Simek. Investigational products undergo a thorough review process as the sponsor prepares to study the safety and effectiveness of the product in adequate and well-controlled human studies (clinical trials).
As part of this review, the sponsor must show how the product will be manufactured so that FDA can make certain that appropriate steps are being taken to help assure the product’s safety, purity and potency. FDA also requires that there be sufficient data generated from animal studies to aid in evaluating any potential risks associated with the use of these products.
Consumers need to be aware that at present–other than cord blood for certain specified indications–there are no approved stem cell products.
Advice for Consumers
- If you are considering stem cell treatment in the U.S., ask your physician if the necessary FDA approval has been obtained or if you will be part of an FDA-regulated clinical study. This also applies if the stem cells are your own. Even if the cells are yours, there are safety risks, including risks introduced when the cells are manipulated after removal.There is a potential safety risk when you put cells in an area where they are not performing the same biological function as they were when in their original location in the body,” says Simek. Cells in a different environment may multiply, form tumors, or may leave the site you put them in and migrate somewhere else.
- If you are considering having stem cell treatment in another country, learn all you can about regulations covering the products in that country. Exercise caution before undergoing treatment with a stem cell-based product in a country that—unlike the U.S.—may not require clinical studies designed to demonstrate that the product is safe and effective. FDA does not regulate stem cell treatments used in solely in countries other than the United States and typically has little information about foreign establishments or their stem cell products.
Thwarting a Stem Cell Scheme
In December, 2011, three men were arrested in the United States and charged with 15 counts of criminal activity related to manufacturing, selling and using stem cells without FDA sanction or approval.
According to the criminal indictment, one of the accused, a licensed midwife who operated a maternity care clinic in Texas, obtained umbilical cord blood from birth mothers, telling them it was for “research” purposes. Instead, the midwife sold the cord blood to a laboratory in Arizona which, in turn, sent the blood to a paid consultant at a university in South Carolina. The owner of the laboratory in Arizona was convicted in August 2011 of unlawfully introducing stem cells into interstate commerce. She faces up to 3 years in prison and a fine of up to $10,000.
The consultant, an assistant professor, used university facilities to manufacture stem cell products. He then sent the products back to the lab, which sold them to a man representing himself as a physician licensed in the U.S. The man then traveled to Mexico to perform unapproved stem cell procedures on people suffering from cancer, multiple sclerosis and other autoimmune diseases.
The three defendants allegedly received more than $1.5 million from patients seeking treatment for incurable diseases.
“Scammers like these offer false hope to people with incurable diseases in order to line their own pockets with money,” says Special Agent in Charge Patrick J. Holland of FDA’s Office of Criminal Investigations (OCI), Kansas City Field Office. “FDA will continue to aggressively pursue perpetrators who expose the American public to the dangers of unapproved stem cells and ensure that they are punished to the full extent of the law.”
FDA’s OCI worked the case with the Federal Bureau of Investigations and the Internal Revenue Service’s Criminal Investigations Division.
This article appears on FDA’s Consumer Updates page, which features the latest on all FDA-regulated products.
- Stem Cells (Medline Plus) has links to overviews, news items, specific conditions, research (including clinical trials and research news from reputable organizations), directories and organizations
- Stem Cell Information(US National Institutes for Health) includes links to
- FDA Warns About Stem Cell Claims – Information You Should Know (regcompliance.wordpress.com)
- Stem Cells: Worldwide Markets for Transplantation, Cord Blood Banking and Drug Development (prnewswire.com)
- American scientist arrested in stem-cell clinic sting (blogs.nature.com)
- FBI crackdown on unproven stem cell therapies (newscientist.com)
- FBI crackdown on unproven stem cell therapies (newscientist.com)
- 3 Arrested for Peddling Miracle Stem Cell Cure (foxnews.com)
- Stem Cell Fraud: A 60 Minutes investigation (cbsnews.com)
- Legislator says stem cells helped ” Times Record News (wingright.org)
- Flexible Adult Stem Cells, Right There In Your Eye (medicalnewstoday.com)
- What Is Autologous Stem Cell Transplantation? (everydayhealth.com)
- Video: Preview: Stem Cell Fraud (cbsnews.com)
- FDA Approves Cord Blood For Stem Cell Transplant (medicalnewstoday.com)
- The FDA, Politics and Journalistic Fraud: The Stem Cell Battle in America (erasetheneed.wordpress.com)
- Texas prepares to fight for stem cells (nature.com)
A drugstore within –Mesenchymal stem cells protect and heal
A stem cell that can morph into a number of different tissues is proving a natural protector, healer and antibiotic maker, researchers at Case Western Reserve University and their peers have found.
Mesenchymal stem cells reaped from bone marrow had been hailed as the key to growing new organs to replace those damaged or destroyed by violence or disease, but have failed to live up to the billing.
Instead, scientists who’d been trying to manipulate the cells to build replacement parts have been finding the cells are innately potent antidotes to a growing list of maladies.
The findings are summarized in the July 8 issue of Cell Stem Cell.
The cell, referred to as an MSC, “is a drugstore that functions at the local site of injury to provide all the medicine that site requires for its successful regeneration,” said Arnold Caplan, professor of biology at Case Western Reserve, and lead author of the paper.
Here’s how: (click here for rest of article)
New Rochelle, NY, June 29, 2011—Sophisticated genetic tools and techniques for achieving targeted gene delivery and high gene expression levels in bone marrow will drive the successful application of gene therapy to treat a broad range of diseases. Examples of these cutting-edge methods are presented in a series of five provocative articles in the latest issue of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. (www.liebertpub.com). The articles are available free online at www.liebertpub.com/hum
Barese and Dunbar highlight the advances in gene marking techniques that are enabling selection and targeting of specific immune cell populations for cell and gene therapy. The success of marking studies will help optimize gene transfer for immunotherapeutics and improve patient survival, conclude the authors in the review article “Contributions of Gene Marking to Cell and Gene Therapies.“….
A sampling of General Stem Cell Web Sites/Resources
- Stem Cell Information (US National Institutes of Health) provides answers to FAQs (as “What are Stem Cells?”), overviews of current research, a glossary, links to additional resources, and more
- MEDLINEplus—Stem Cells/Stem Cell Transplantation -A consumer health database that includes news, health resources, clinical trials, and more.
- Adult Stem Cell Research Network An internet-based project of The Cell Therapy Foundation designed to be a well-maintained and reliable source of information for the public regarding adult stem cell research, as well as to be a community of practice and collaboration among fellow researchers.
- A Stem Cell Story This 15-minute movie from EuroStemCell introduces the world of stem cell research and is available as a video podcast.
- ExploreStemCells A UK resource for the general public that discusses the use of stem cells in medical treatments and therapies.
- How Embryonic Stem Cell Lines Are Made An online animation from the Dolan DNA Learning Center, Cold Spring Harbor Laboratory. (Requires Adobe Flash Player)
- Human Embryonic Stem Cells An animated tutorial for the general public. (RequiresAdobe Flash Player)
- Advances in delivery of therapeutic genes to treat brain tumors (sciencedaily.com)
- New gene therapy fixes mistakes (sciencenews.org)
- Genome Editing Improves Blood Clotting in Mice with Hemophilia B (nextbigfuture.com)
- Scientists discover new airway stem cell (scienceblog.com)
- Adult stem cells can help win battle of the bulge (news.bioscholar.com)
- Researchers develop new gene therapy for heart failure (medicalxpress.com)
- Robert Lanza cures blindness with stem cell therapy (itoddaily.com)
- Researchers rebut critiques of stem cells derived from adult cells (blogs.nature.com)
- Advances in delivery of therapeutic genes to treat brain tumors (medicalxpress.com)
- Mount Sinai School of Medicine’s New Gene Therapy Proves Effective in Treating Severe Heart Failure (nextbigfuture.com)
- Genome editing, a next step in genetic therapy, corrects hemophilia in animals (physorg.com)