Bone Marrow Transplant Shrinks Enlarged Hearts

For the first time, researchers have been able to show that injections of stem cells into enlarged hearts reduced heart size and scar tissue, and improved function to injured areas of the heart. This small trial was published in Circulation Research: Journal of the American Heart Association. While this research is in the early stages, these findings hold tremendous promise for the more than five million Americans who have enlarged hearts due to damage sustained from heart attacks. Heart patients suffer from premature death and have major disabilities. Heart attack patients also experience frequent hospitalizations. Treatment options are also limited to lifelong medications and major medical interventions like heart transplantation.

By using catheters, these researchers injected stem cells derived from the patient’s own bone marrow into the hearts of eight men (average age 57), wll of whom suffered from chronically enlarged, low-functioning hearts. Joshua M. Hare, M.D., the study’s senior author and professor of medicine and director of the Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, University of Miami in Miami, Fla, said, “The injections first improved function in the damaged area of the heart and then led to a reduction in the size of the heart. This was associated with a reduction in scar size. The effects lasted for a year after the injections, which was the full duration of the study.”

Specifically, these data showed that 1) heart size decreased an average of 15 percent to 20 percent, which is about three times what is possible with current medical therapies; 2) scar tissue decreased by an average of 18.3 percent and; 3) there was dramatic improvement in the function, or contraction, of specific heart areas that were damaged.

Hare continued, “This therapy improved even old cardiac injuries. Some of the patients had damage to their hearts from heart attacks as long as 11 years before treatment.”

The researchers had used two different types of bone marrow stem cells in their study — “mononuclear” (bulk bone marrow stem cells) or mesenchymal stem cells. The study lacked the power to determine if one type of cell works better than the other, but all patients in the study benefited from the therapy and tolerated the injections with no serious adverse events.

Hare’s study assessed the effect of stem cell injections differently from other studies of post-heart attack stem cell treatment. His team measured contractility, scar size and structural changes of the heart. “Studies of bone marrow cell therapy for ischemic heart disease in animals have shown improved ejection fraction (the amount of blood the heart can pump). However, this measurement has not reliably translated to early phase studies in humans,” Hare said. “Ejection fraction may not be the best way to measure the success of stem cell therapy in the human heart.”

Hare also said their findings suggest that patients’ quality of life could improve as the result of this therapy because the heart is a more normal size and functions better. Hare cautioned, “we have yet to prove this clinical benefit – this is an experimental therapy in phase one studies. These findings support further clinical trials and give us hope that we can help people with enlarged hearts.”

Cerebrospinal fluid directs neural stem cell development

The clear, watery substance that bathes the brain and spinal cord is called cerebrospinal fluid.  This fluid is crucial for transporting gases and nutrients to the central nervous system, but it also turns out to affect neural stem cells.

Howard Hughes Medical Institute (HHMI) investigator Christopher Walsh, and his postdoctoral fellow Maria Lehtinen, former student Mauro Zappaterra, and colleagues have discovered that cerebrospinal fluid or CSF contains a complex mix of proteins that changes dramatically with age. In the lab, CSF by itself is enough to support the growth of neural stem cells, and this effect is particularly robust in young brains.

Additionally, these experiments discovered that the protein make-up of CSF in people with malignant brain cancer is different from that of healthy people.  “This suggests that the CSF can make a more supportive or less supportive environment for tumor growth,” notes Walsh, Chief of Genetics at Children’s Hospital Boston. The work is published in the March 10, 2011, issue of the journal Neuron.

Today, most researchers think of it as a relatively simple salt solution that gives the brain buoyancy and helps protect it from knocking against the skull.  However, several years ago, research on brain development conducted by Walsh’s group showed that there is much more to CSF.  Walsh and his colleagues noticed that neural stem cells tend to line up around the brain’s inner chambers, where CSF is stored, and stick cellular fingers, called cilia, into the pool of CSF. “That made us think, there’s got to be something in CSF that’s binding to cilia and controlling how the cell divides,” Walsh says.

In 2007, Zappaterra and Walsh performed the first comprehensive analysis of embryonic human CSF. Embryonic human CSF contains hundreds of different proteins, including proteins that influence cell growth, transport, support, and signaling. Walsh said, “We were amazed at the diversity of substances that we identified in there, many of which people had no clue would be there.”

In this new study, Walsh and his colleagues isolated small sections of embryonic rat brain tissue and cultured them with CSF from rats of different ages. When brain stem cells were bathed in CSF from young rats, they furiously divided, but when grown on CSF from older rats, there is less cell division.  Nevertheless, CSF from all ages contained all that is needed to maintain brain stem cells in a dish. Subsequent analysis of the fluid showed that the amount of a protein called Insulin-like growth factor 2 (Igf2) strongly correlates with the level of cell division, suggesting that this protein can be used to stimulate the division of neural stem cells in older patients.

The researchers then teamed up with Eric Wong’s groupfrom Beth Israel Deaconess Medical Center that has a bank of CSF samples isolated from people with various stages of glioblastoma, a type of brain cancer in which tumors infiltrate the whole brain. Wong’s group found that people with more advanced cancer have higher levels of Igf2 in CSF than do those with less severe forms of the disease.

It is presently still unknown if the increase in Igf2 levels is partly causing the cancer, or is instead a consequence of living with the disease. “We certainly don’t think Igf2 is the only contributor to the pathology, because glioblastomas are very complex. But it may be an interesting biomarker to consider,” says Maria Lehtinen, who is a joint first author of the study, along with Zappaterra.

Taking a closer look at CSF could be helpful in other brain diseases as well. Some researchers are investigating whether the levels of certain proteins, like Tau and Beta amyloid, might be used as predictors of Alzheimer’s disease, for example.

Because CSF is made by a tiny knob in the brain’s chambers called the choroid plexus,which constitutes the interface between the bloodstream and the brain—it could explain part of the mystery of how changes in the body link up to the brain. For example, if you exercise a lot, you form more brain cells, but no one knows exactly how this works.

A new type of stem cell

A research team at Sanford-Burnham Medical Research Institute (Sanford-Burnham), Chung-Ang University in Korea, the University of British Columbia, Harvard Medical School have found what might be a better way to regenerate lost tissue in order to treat conditions like heart disease and stroke.   In the March 4th edition of the Proceedings of the National Academy of Sciences, they outline a method to obtain a new kind of stem cell they call and “induced conditional self-renewing progenitor (ICSP) cell.”

With the addition of a single gene, the team reprogrammed neural progenitor cells (brain cells that can generate other types of brain cells) to self-renew in a laboratory dish.  Once the cells had grow to the proper density, the researchers moved the ICSP cells into laboratory rodents that had suffered strokes.  Inside the brains of those laboratory animals, the cells stopped proliferating and started differentiating into brain cells.  They also made connections with other brain cells and improved brain function.

“It’s amazingly cool that we can dial adult cells all the way back to embryonic-like stem cells, but there are a lot of issues that still need to be addressed before iPS cells can be used to treat patients,” said Evan Y. Snyder, M.D., Ph.D., director of Sanford-Burnham’s Stem Cells and Regenerative Biology Program and corresponding author of the study. “So we wondered… if we just want to treat a brain disease, do we really have to start with a skin cell, which has nothing to do with the brain, and push it all the way back to the point that it has potential to become anything? In this study, we developed ICSP cells using a cell from the organ we’re already interested in—the nervous system, in this case—and pushed it back just enough so it continued to divide, giving us a quantity that we were able to apply efficiently, safely and effectively to treat stroke injury in a rodent model.”

Here’s how ICSP cells work.  Researchers use modified viruses to introduce a gene called v-Myc into neural progenitor cells.  Myc, one of four standard genes already used to generate iPS cells, triggers self-renewal, guiding cells through the replication process.  Scientists are sometimes cautious when it comes to adding genes like Myc—if cells keep dividing after transplantation in a patient, cancer could develop—but v-Myc is known to be safer than other flavors of the Myc gene. What’s more, the v-Myc gene in this case is conditionally expressed. This means that ICSP cells can only produce v-Myc when the researchers add a compound called tetracycline to laboratory cultures. When tetracycline is removed, the cells cease dividing and start differentiating. Once transplanted into to an animal model, ICSP cells are no longer exposed to tetracycline and take their growth and differentiation cues from their new environment.

In this study, ICSP cells differentiated into active neurons and other brain cell types with therapeutic payoff for the adult rats that had suffered intracerebral hemorrhagic stroke.  Those rodents that had received the ICSPs showed improved behavioral performance. Although the long-term genomic stability of ICSP cells remains to be seen, no adverse effects have arisen over five months of observation. The team envisions that this ICSP approach will also extend to progenitor cells obtained from other organs, such as heart, pancreas, or muscle, potentially accelerating the use of stem cell therapies for a broad range of diseases.

56-year old returns to the ski slopes after stem cell treatment

The longest ski run in the world is the Vallée Blanche on the Aguille du Midi, in Chamonix, France, which is 17 km (10.6 miles) long. A 56-year-old international businessman, who goes by the initials “CM,” injured his knee while running to catch a plane. An orthopedic surgeon saw him in late 2009, after experiencing 9 months of unrelenting knee pain that caused him to limp and prevented him from sleeping. MRI exams showed tears in both the medial and lateral meniscus and swelling under the knee cap.

His physician said that arthroscopic surgery that cut out pieces of the meniscus was more likely to cause knee arthritis and a need for an early knee replacement. He contacted Regenexx Corporation for a mesenchymal stem cell transplant.

The results? Go here for a video that shows him skiing the world’s hardest ski run after surgery.

Stem Cells for a Golfer’s Knee

A 57-year-old golfer with severe arthritis in his knees received two stem cell treatments that consisted of transplantation of his own mesenchymal stem cells that had been extracted, cultured, amplified, and placed into his knee-joint. Now eleven weeks after his treatment, he can walk 6-7 miles while playing golf, carrying his clubs, four time each week, without any pain.

Read about it here.