From organs to muscle tissue: how stem cells are being used in 3D

A Sunday Afternoon on the Island of La Grande Jatte by Georges-Pierre Seurat

When most people think of stem cells, they might conjure up an image of small dots under a microscope. It is hard to imagine these small specs being applied to three-dimensional structures. But like a pointillism painting, such as A Sunday Afternoon on the Island of La Grande Jatte by Georges-Pierre Seurat, stem cells can be used to help build things never thought possible. Two studies demonstrate this concept in very different ways.

MIT engineers have designed coiled “nanoyarn,” shown as an artist’s interpretation here. The twisted fibers are lined with living cells and may be used to repair injured muscles and tendons while maintaining their flexibility. Image by Felice Frankel

A study at MIT used nanofiber coated with muscle stem cells and mesenchymal stem cells in an effort to provide a flexible range of motion for these stem cells. Hundreds of thousands of nanofibers were twisted, resembling yarn and rope, in order to mimic the pattern found in tendons and muscle tissue throughout the body. The researchers at MIT found that the yarn like structure of the nanofibers keep the stem cells alive and growing, even as the team stretched and bent the fibers multiple times.

Normally, when a person injures these types of tissues, particularly around a major joint such as the shoulder or knee, it require surgery and weeks of limited mobility to heal properly. The MIT team hopes that their technology could be applied toward treating the site of injury while maintaining range of motion as the newly applied stem cells continue to grow to replace the injured tissue.

In an article, Dr. Ming Guo, assistant professor of mechanical engineering at MIT and one of the authors of the study, was quoted as saying,

“When you repair muscle or tendon, you really have to fix their movement for a period of time, by wearing a boot, for example. With this nanofiber yarn, the hope is, you won’t have to wearing anything like that.”

Their complete findings were published in the Proceedings of the National Academy of Sciences (PNAS).

Researchers in Germany have created transparent human organs using a new technology that could pave the way to print three-dimensional body parts such as kidneys for transplants. Above, Dr. Ali Ertuerk inspects a transparent human brain.
Photo courtesy of Reuters.

In a separate study, researchers in Germany have successfully created transparent human organs, paving the way to print three-dimensional body parts. Dr. Ali Erturk at Ludwig Maximilians University in Munich, with a team of scientists, developed a technique to create a detailed blueprint of organs, including blood vessels and every single cell in its specific location. These directions were then used to print a scaffold of the organ. With the help of a 3D printer, stem cells, acting like ink in a printer, were injected into the correct positions to make the organ functional.

Previously, 3D-printed organs lacked detailed cellular structures because they were based on crude images from computer tomography or MRI machines. This technology has now changed that.

In an article, Dr. Erturk is quoted as saying,

“We can see where every single cell is located in transparent human organs. And then we can actually replicate exactly the same, using 3D bioprinting technology to make a real functional organ. Therefore, I believe we are much closer to a real human organ for the first time now.”

Mechanical forces are the key to speedy recovery after blood cancer treatment

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Mesenchymal stem cells grown on a surface with specialized mechanical properties. Image courtesy of Krystyn Van Vliet at MIT.

Blood cancers, such as leukemia and lymphoma, are projected to be responsible for 10% of all new cancer diagnoses this year. These types of cancers are often treated by killing the patient’s bone marrow (the site of blood cell manufacturing), with a treatment called irradiation. While effective for ridding the body of cancerous cells, this treatment also kills healthy blood cells. Therefore, for a time after the treatment, patients are particularly vulnerable to infections, because the cellular components of the immune system are down for the count.

Now scientists at MIT have devised a method to make blood cells regenerate faster and  minimize the window for opportunistic infections.

Using multipotent stem cells (stem cells that are able to become multiple cell types) grown on a new and specialized surface that mimics bone marrow, the investigators changed the stem cells into different types of blood cells. When transplanted into mice that had undergone irradiation, they found that the mice recovered much more quickly compared to mice given stem cells grown on a more traditional plastic surface that does not resemble bone marrow as well.

This finding, published in the journal Stem Cell Research and Therapy, is particularly revolutionary, because it is the first time researchers have observed that mechanical properties can affect how the cells differentiate and behave.

The lead author of the study attributes the decreased recovery time to the type of stem cell that was given to mice compared to what humans are normally given after irradiation. Humans are given a stem cell that is only able to become different types of blood cells. The mice in this study, however, were give a stem cell that can become many different types of cells such as muscle, bone and cartilage, suggesting that these cells somehow changed the bone marrow environment to promote a more efficient recovery. They attributed a large part of this phenomenon to a secreted protein call ostepontin, which has previously been describe in activating the cells of the immune system.

In a press release, Dr. Viola Vogel, a scientist not related to study, puts the significance of these findings in a larger context:

“Illustrating how mechanopriming of mesenchymal stem cells can be exploited to improve on hematopoietic recovery is of huge medical significance. It also sheds light onto how to utilize their approach to perhaps take advantage of other cell subpopulations for therapeutic applications in the future.”

Dr. Krystyn Van Vliet, explains the potential to expand these findings beyond the scope of just blood cancer treatment:

“You could imagine that by changing their culture environment, including their mechanical environment, MSCs could be used for administration to target several other diseases such as Parkinson’s disease, rheumatoid arthritis, and others.”

 

Stem Cell Roundup: better model of schizophrenia, fasting boosts stem cells, and why does our hair gray.

Stem cell photo of the week:
Recreating brain cell interactions for studying schizophrenia

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Salk researchers used stem cells to derive CA3 pyramidal neurons (green), including a rare subtype of the cells (red). Image: Salk Institute

Our pick for the stem cell image of the week is from the laboratory of Rusty Gage at the Salk Institute. The team generated multiple types of nerve cells from stem cells to more closely represent the interactions that occur in the brain. They’re using this system to show how the communication between these nerve cells becomes faulty in people with schizophrenia. A Salk Institute press release provides more details about their study which was published in Cell Stem Cell.

Regenerative power of intestinal stem cells maintained via fasting
For many decades, researchers have known that restricting food intake in mice can extend life span. Why it happens hasn’t been well understood. This week, a team at MIT uncovered a possible explanation: fasting increases the regenerative power of stem cells.

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Intestinal stem cells from mice that fasted for 24 hours, at right, produced much more substantial intestinal organoids than stem cells from mice that did not fast, at left.
Image: Maria Mihaylova and Chia-Wei Cheng, MIT

The report, published in Cell Stem Cell, focused on the well-studied intestinal stem cell, which renews the intestinal lining every five days. As we age, the intestinal stem cell’s regenerative abilities wane and damage to the intestinal lining takes longer to repair.

Mice were fasted for 24 hours and then their intestinal stem cells were retrieved and grown into mini-intestine organoids in petri dishes. According to Maria Mihaylova, PhD, one of the lead authors, the results of the experiment were very clear:

“It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven,” Mihaylova said in a press release. “This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this.”

Mihaylova and the team went on to show that fasting caused the stem cells to burn fat instead of carbohydrates for their energy needs. Inhibiting the gene pathways that flip this metabolic switch also blocks the regenerative capacity of fasting. On the other hand, molecules that boost the gene pathways mimic the effects of fasting without changing food intake. This intriguing finding could potentially have clinical applications for cancer patients who suffer intestinal injury from the toxic effects of chemotherapy drugs but who certainly aren’t in a condition to fast.

Premature graying, our immune system and stem cells: a surprising link. (Kevin McCormack)
As someone whose hair went gray at a relatively young age – well, it seemed young to me! – this next story naturally caught my eye. It highlights how our immune systems may play a key role in determining our hair color and, in particular, when that hair turns gray.

Our bodies are constantly shedding hairs and replacing them with new ones. Normally stem cells called melanocytes help ensure the new hairs have your original color, be it black, blonde, brunette or red.

Researchers at the National Institutes of Health and the University of Alabama, Birmingham, found that when the body is attacked by a virus, our immune system kicks in and respond by producing interferon to fight off the infection. However, when a protein called MITF, that is involved in regulating how cells use interferon, fails to work properly it can also affect melanocytes causing them to lose their pigmentation. Without that pigmentation the new hairs are gray.

The study, which appears in the journal PLOS Biology, is too late to help me and my gray hair – particularly as it was done in mice – but it could pave the way for further research that identifies how genes that control pigment in our hair and skin also control our immune system.

Cancer-causing mutations in blood stem cells may also link to heart disease

Whether we read about it in the news or hear it from our doctor, when we think about the causes of heart disease it’s usually some combination of inheriting bad genes from our parents and making poor life style choices like smoking or eating a diet high in fat and cholesterol. But in a fascinating research published yesterday in the New England Journal of Medicine, scientists show evidence that in some people, heart disease may develop much in the same way that a blood cancer does; that is, through a gradual, lifetime accumulation of mutations in hematopoietic cells, or blood stem cells.

This surprising discovery began as a project, published in 2014, aimed at early detection of blood cancers in the general population. This earlier study focused on the line of evidence that cells don’t become cancerous overnight but rather progress slowly as we age. So, in the case of a blood cancer, or leukemia, a blood stem cell can acquire a mutation that transforms the cell into a pre-cancerous state. When that stem cell multiplies it creates “clones” of the blood stem cell that had the cancer-initiating mutation. It’s only after additional genetic insults that these stem cells become full blown cancers.

The research team, composed of scientists from Brigham and Women’s Hospital as well as the Broad Institute of Harvard and MIT, examined DNA sequences from blood samples of over 17,000 people who didn’t have blood cancer. They analyzed these samples, specifically looking at 160 genes that are often mutated in blood cancer. The results from the 2014 study showed that mutations in these genes in people 40 years and under were few and far between. Interestingly, the frequency noticeably increased in older folks with those 10% over 70 years of age carrying the mutations.

Most of these so-called “clonal hematopoiesis of indeterminate potential”, or CHIP, mutations occurred in three genes called DNMT3A, TET2, and ASXL1. While these mutations were indeed associated with a 10-fold higher risk of blood cancer, the team also saw an unexpected correlation: people with these mutations had a 40% higher overall risk of dying due to other causes compared to those who did not carry the mutations. They pinpointed heart disease as one primary cause of the increased mortality risk.

The current follow-up study not only sought to confirm this correlation between the mutations and heart disease but also show the mutations cause the increased risk. This time around, the team looked for the mutations in a group of four different populations totaling over 8000 people. Again, they saw a correlation between the mutations and the risk of heart disease or a heart attack later in life. One of the team leads, Dr. Sekar Kathiresan from the Broad Institute, talked about his team’s reaction to these results in a Time Magazine interview:

Sekar Kathiresan, Photo: Broad Institute

“We were fully expecting not to find anything here. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.”

 

To show a causal link, they turned to mouse studies. They collected bone marrow stem cells from mice engineered to lack Tet2, one of the three genes that when mutated had been associated with increased risk of heart disease. The bone marrow cells were then transplanted into mice which are prone to have increased blood cholesterol and symptoms of heart disease. The presence of these cells that lacked Tet2 led to increased hardening of major arteries – a precursor to clogged blood vessels, heart disease and heart attacks – compared to mice that received normal bone marrow cells.

Though more work remains, Kathiresan thinks these current results offer some tantalizing therapeutic possibilities:

“This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking. And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.”

MIT Scientists Recreate Malaria in a Dish to Test Promising Drug Candidates

At the beginning, it feels like the flu: aches, pains and vomiting. But then you begin to experience severe cold and shivering, followed by fever and sweating—a cycle, known as tertian fever, that repeats itself every two days. And that’s when you know: you’ve contracted malaria.

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

But you wouldn’t be alone. According to the World Health Organization, nearly 200 million people, mostly in Africa, contracted the disease in 2013. Of those, nearly half a million—mainly children—died. There is no cure for malaria, and the parasites that cause the disease are quickly developing resistance to treatments. This is a global public health crisis, and experts agree that in order to halt its spread, they must begin thinking outside the box.

Enter Sangeeta Bhatia, renowned biomedical engineer from the Massachusetts Institute of Technology (MIT)—who, along with her team, has devised a quick and easy way to test out life-saving drug candidates that could give doctors and aid workers on the front lines fresh ammunition.

One of the key hurdles facing scientists has been the nature of the disease’s progression itself. Caused by parasites transmitted via infected mosquitos, the disease first takes hold in the liver. It is only after a few weeks that it enters the blood stream, causing symptoms. By then, the disease is so entrenched within the patient that complete eradication is extremely difficult. Even if the patient recovers, he or she will likely suffer relapses weeks, months or even years later.

The trick, therefore, is to catch the disease before it enters the blood stream. To that effect, several promising drugs have been put forth, and scientists are eager to test them out on liver tissue infected with malaria. Except that they can’t: liver tissue donors are few and far between, and lack the genetic diversity needed for large-scale testing.

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

So Bhatia and her team developed a new solution: they’d make the cells themselves. Reporting in today’s issue of Stem Cell Reports, the team describes how they transformed human skin cells into liver cells, by way of induced pluripotent stem cell (iPS cell) technology. Then, by infecting these cells with the malaria parasite, they could test a variety of drug candidates to see which worked best. As Bhatia explained:

“Our platform can be used for testing candidate drugs that act against the parasite in the early liver stages, before it causes disease in the blood and spreads back to the mosquito vector. This is especially important given the increasing occurrence of drug-resistant strains of malaria in the field.”

Bhatia has long been known for finding innovative solutions to longstanding issues in science and medicine. Just last year, she was awarded the prestigious Lemelson-MIT Prize in part for her invention of a paper-based urine test for prostate cancer.

In this study, the researchers bombarded malaria-infected liver cells with two drugs, called atovaguone and primaquine, each developed to treat the disease specifically at the liver stage.

The results, though preliminary, are promising: the cells responded well to both drugs, underscoring the value of this approach to testing drugs—an approach that many call “disease in a dish.”

The potential utility of “disease in a dish” studies cannot be understated, as it gives researchers the ability to screen drugs on cells from individuals of varying genetic backgrounds, and discover which drug, or drugs, works best for each group.

Shengyong Ng, a postdoctoral researcher in Bhatia’s lab, spoke of what this study could mean for disease research:

“The use of iPSC-derived liver cells to model liver-stage malaria in a dish opens the door to study the influence of host genetics on antimalarial drug efficacy, and lays the foundation for their use in antimalarial drug discovery.”

Find out more about how scientists use stem cells to model disease in a dish in our video series, Stem Cells In Your Face.