Cardiac Stem Cell Therapy may Heal Heart Damage Caused by Duchenne Muscular Dystrophy

Late-breaking basic science research presented at American Heart Association Scientific Sessions shows stem cell treatment restores heart function damaged by muscular disease

Tuesday, 18 November 2014

Researchers at the Cedars-Sinai Heart Institute have found that injections of cardiac stem cells might help reverse heart damage caused by Duchenne muscular dystrophy, potentially resulting in a longer life expectancy for patients with the chronic muscle-wasting disease.

The study results were presented today at a Breaking Basic Science presentation during the American Heart Association Scientific Sessions in Chicago. After laboratory mice with Duchenne muscular dystrophy were infused with cardiac stem cells, the mice showed steady, marked improvement in heart function and increased exercise capacity.

Duchenne muscular dystrophy, which affects 1 in 3,600 boys, is a neuromuscular disease caused by a shortage of a protein called dystrophin, leading to progressive muscle weakness. Most Duchenne patients lose their ability to walk by age 12. Average life expectancy is about 25. The cause of death often is heart failure because the dystrophin deficiency leads to cardiomyopathy, a weakness of the heart muscle that makes the heart less able to pump blood and maintain a regular rhythm.

"Most research into treatments for Duchenne muscular dystrophy patients has focused on the skeletal muscle aspects of the disease, but more often than not, the cause of death has been the heart failure that affects Duchenne patients," said Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute and study leader.

"Currently, there is no treatment to address the loss of functional heart muscle in these patients."

During the past five years, the Cedars-Sinai Heart Institute has become a world leader in studying the use of stem cells to regenerate heart muscle in patients who have had heart attacks. In 2009, Marbán and his team completed the world's first procedure in which a patient's own heart tissue was used to grow specialized heart stem cells. The specialized cells were then injected back into the patient's heart in an effort to repair and regrow healthy muscle in a heart that had been injured by a heart attack. Results, published in The Lancet in 2012, showed that one year after receiving the experimental stem cell treatment, heart attack patients demonstrated a significant reduction in the size of the scar left on the heart muscle.

Earlier this year, Heart Institute researchers began a new study, called ALLSTAR, in which heart attack patients are being infused with allogeneic stem cells, which are derived from donor-quality hearts.

Recently, the Heart Institute opened the nation's first Regenerative Medicine Clinic, designed to match heart and vascular disease patients with appropriate stem cell clinical trials being conducted at Cedars-Sinai and other institutions.

"We are committed to thoroughly investigating whether stem cells could repair heart damage caused by Duchenne muscular dystrophy," Marbán said.

In the study, 78 lab mice were injected with cardiac stem cells. Over the next three months, the lab mice demonstrated improved pumping ability and exercise capacity in addition to a reduction in heart inflammation. The researchers also discovered that the stem cells work indirectly, by secreting tiny fat droplets called exosomes. The exosomes, when purified and administered alone, reproduce the key benefits of the cardiac stem cells.

Marbán said the procedure could be ready for testing in human clinical studies as soon as next year. The process to grow cardiac-derived stem cells was developed by Marbán when he was on the faculty of Johns Hopkins University. Johns Hopkins has filed for a patent on that intellectual property and has licensed it to Capricor, a company in which Cedars-Sinai and Marbán have a financial interest. Capricor is providing funds for the ALLSTAR clinical trial at Cedars-Sinai.

The Cedars-Sinai Heart Institute has been at the forefront of developing investigational stem cell treatments for heart attack patients.

Source: Cedars-Sinai Medical Center

Contact: Sally Stewart

.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

---

Vesicles Influence the Function of Nerve Cells

Neurons react to the transmission activity of exosomes on three fundamental levels

Tuesday, 07 October 2014

The JGU researchers were able to show that

exosomes are absorbed by the nerve cells and

thus help protect these against stress. Credit:

Institute of Molecular Cell Biology. 

Tiny vesicles containing protective substances which they transmit to nerve cells apparently play an important role in the functioning of neurons. As cell biologists at Johannes Gutenberg University Mainz (JGU) have discovered, nerve cells can enlist the aid of mini-vesicles of neighbouring glial cells to defend themselves against stress and other potentially detrimental factors. These vesicles, called exosomes, appear to stimulate the neurons on various levels: they influence electrical stimulus conduction, biochemical signal transfer, and gene regulation. Exosomes are thus multifunctional signal emitters that can have a significant effect in the brain.

Neurons (blue) which have absorbed exosomes

(green) have increased levels of the enzyme

catalase (red), which helps protect them against

peroxides. Credit: Institute of Molecular Cell

Biology, JGU.

The researchers in Mainz already observed in a previous study that oligodendrocytes release exosomes on exposure to neuronal stimuli. These exosomes are absorbed by the neurons and improve neuronal stress tolerance. Oligodendrocytes are a type of glial cell and they form an insulating myelin sheath around the axons of neurons. The exosomes transport protective proteins such as heat shock proteins, glycolytic enzymes, and enzymes that reduce oxidative stress from one cell type to another, but also transmit genetic information in the form of ribonucleic acids.

"As we have now discovered in cell cultures, exosomes seem to have a whole range of functions," explained Dr. Eva-Maria Krämer-Albers. By means of their transmission activity, the small bubbles that are the vesicles not only promote electrical activity in the nerve cells, but also influence them on the biochemical and gene regulatory level.

Cultivated neurons on a multielectrode array

chip: the electrodes register the electrical

impulses of the neurons. Credit: Institute of

Physiology, Mainz University Medical Center.

"The extent of activities of the exosomes is impressive," added Krämer-Albers. The researchers hope that the understanding of these processes will contribute to the development of new strategies for the treatment of neuronal diseases. Their next aim is to uncover how vesicles actually function in the brains of living organisms.

Source: Johannes Gutenberg Universitaet Mainz

Contact: Dr. Eva-Maria Krämer-Albers

Reference:

Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation

Dominik Fröhlich, Wen Ping Kuo, Carsten Frühbeis, Jyh-Jang Sun, Christoph M. Zehendner, Heiko J. Luhmann, Sheena Pinto, Joern Toedling, Jacqueline Trotter and Eva-Maria Krämer-Albers

Philosophical Transactions of the Royal Society B, 18 August 2014 DOI: 10.1098/rstb.2013.0510

.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

---

Researchers Identify How Heart Stem Cells Orchestrate Regeneration

Exosomes, tiny 'bubbles' secreted by specialized cardiac stem cells, appear to carry 'instructions' that spur heart cells to regenerate following heart attack

Wednesday, 07 May 2014

Investigators at the Cedars-Sinai Heart Institute – whose previous research showed that cardiac stem cell therapy reduces scarring and regenerates healthy tissue after a heart attack in humans – have identified components of those stem cells responsible for the beneficial effects.

In a series of laboratory and lab animal studies, Heart Institute researchers found that exosomes, tiny membrane-enclosed "bubbles" involved in cell-to-cell communication, convey messages that reduce cell death, promote growth of new heart muscle cells and encourage the development of healthy blood vessels.

"Exosomes were first described in the mid-1980s, but we only now are beginning to appreciate their potential as therapeutic agents. We have found that exosomes and the cargo they contain are crucial mediators of stem cell-based heart regeneration, and we believe this might lead to an even more refined therapy using the 'active ingredient' instead of the entire stem cell," said Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute and a pioneer in developing investigational cardiac stem cell treatments.

"The concept of exosome therapy is interesting because it could potentially shift our strategy from living-cell transplantation to the use of a non-living agent," he added.

"Stem cells must be carefully preserved to keep them alive and functioning until the time of transplant, and there are some risks involved in cell transplantation. In contrast, exosome therapy may be safer and simpler and based on a product with a longer shelf life."

In lab experiments, the researchers isolated exosomes from specialized human cardiac stem cells and found that exosomes alone had the same beneficial effects as stem cells. Exosomes also produced the same post-heart attack benefits in mice, decreasing scar size, increasing healthy heart tissue and reducing levels of chemicals that lead to inflammation. Even when exosomes were injected in mice after heart attack scars were well-established, and traditionally viewed as "irreversible," they brought about multiple structural and functional benefits.

Exosomes transport small pieces of genetic material, called microRNAs, which enable cells to communicate with neighbouring cells to change their behaviour. The researchers pinpointed one such microRNA – one that is especially plentiful in cardiac stem cell exosomes – as responsible for some of the benefits. It is likely, they believe, that this and other microRNAs in the exosomes work together to produce the regenerative effects.

"The exosomes appear to contain the signalling information needed to regenerate healthy heart tissue, they are naturally able to permeate cells, and they have a coating that protects their payloads from degradation as they shuttle from cell to cell," said Marbán, senior author of an article in the May 6, 2014 Stem Cell Reports.

"Injecting exosomes derived from specialized cardiac stem cells may be an attractive alternative to the transplantation of living cells."

Marbán and his clinical and research teams in 2009 performed the first procedure in which a heart attack patient's heart tissue was used to grow specialized stem cells that were injected back into the heart. In 2012, they reported results of a clinical trial that found significant reduction in the size of heart attack-caused scars in patients who underwent the experimental stem cell procedure, compared to others who did not.

They also published findings from an animal study showing that the effect of stem cell therapy following heart attack is indirect – the stem cells themselves do not survive long after being placed in the heart, but they cause enduring effects by stimulating the rapid growth of surviving heart tissue and attracting stem cells already in the heart, which mature into functional heart cells.

The new study sheds light on the underlying mechanisms, crediting stem cell exosomes and the communications cargo they carry for orchestrating regeneration to repair heart attack damage.

The process to grow cardiac-derived stem cells was developed earlier by Marbán when he was on the faculty of Johns Hopkins University. The university has filed for a patent on that intellectual property and has licensed it to Capricor Inc., a biotechnology company in which Marbán is a founder and equity holder. Cedars-Sinai has filed for a patent for the exosome discovery and has licensed it to Capricor. The company provided no funding for this study.

Source: Cedars-Sinai Medical Center 

Contact: Sally Stewart

Reference:

Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy

Ahmed Gamal-Eldin Ibrahim, Ke Cheng, Eduardo Marbán

Stem Cell Reports, 6 May 2014, Volume 2, Issue 5, p606–619

.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

---