Kotlikoff lab

Optogenetic proteins enable visualization of a developing heart.

New technologies involving optogenetic proteins, which use light to control and observe cells with unprecedented precision, have begun to illuminate processes underlying cellular behavior and the effects of cell- and gene-based therapies. Cornell researchers are developing advanced forms of these proteins to create a toolkit to make them more widely available to scientists.

With a five-year, $3.1 million grant from the National Institutes of Healths Heart, Lung and Blood Institute, the team will develop the Cornell Heart, Lung and Blood Resource for Optogenetic Mice (CHROMus), which will incorporate optogenetic proteins in mice and human stem cells. Scientists use such tools to control and observe how different types of cells function and interact.

We will target these tools so that they can be combined to study diseases of the heart, lungs, vasculature and blood, said Dr. Michael Kotlikoff, the Austin O. Hooey Dean of Veterinary Medicine at Cornells College of Veterinary Medicine and the projects lead investigator. Researchers will be able to use them to address a broad set of health issues, including heart attack, stroke, asthma and immune diseases.

Marrying optics and genetics, optogenetics enables scientists to use light to trigger and monitor the behavior of cells engineered to contain one or both of two types of designer proteins: effectors, which respond to light by activating the cell they are on, or sensors, which fluoresce when a cell has been activated.

Effectors and sensors can be engineered into specific kinds of cells and color-coded, letting scientists noninvasively trigger one type to see how another type responds. One can see different cell types light up in living animals, giving direct insight into specific cells roles in complex biological systems.

The lines of CHROMus mice developed in this project are designed to be easily crossbred, creating a combinatorial platform that will allow scientists to customize sets of effectors and sensors including new sensors from the Kotlikoff lab into the specific cell types they want to study.

For example, our lab is particularly interested in using these tools to study the control of blood flow to tissues what happens before, during and after major events like stroke and cardiac infarction, and how abnormal rhythms develop after heart injury, said Kotlikoff. Arrhythmias following a heart attack are the single most common cause of acute death in the western world, and how they can be prevented requires a better understanding of how, why and where they arise. Optogenetic tools let us look directly at relevant cells throughout the heart to determine their role in these dangerous and often fatal events.

The tools will be designed to allow scientists to ask and answer similar questions related to vascular and lung diseases, such as the role of the immune system in asthma and stroke, and how therapeutic stem cells integrate within the tissue that they are designed to repair.

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Optogenetics shed light on cardiac, lung, immune disease

23 hours ago

What if repairing large segments of damaged muscle tissue was as simple as mobilizing the body's stem cells to the site of the injury? New research in mice and rats, conducted at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine, suggests that "in body" regeneration of muscle tissue might be possible by harnessing the body's natural healing powers.

Reporting online ahead of print in the journal Acta Biomaterialia, the research team demonstrated the ability to recruit stem cells that can form muscle tissue to a small piece of biomaterial, or scaffold that had been implanted in the animals' leg muscle. The secret to success was using proteins involved in cell communication and muscle formation to mobilize the cells.

"Working to leverage the body's own regenerative properties, we designed a muscle-specific scaffolding system that can actively participate in functional tissue regeneration," said Sang Jin Lee, Ph.D., assistant professor of regenerative medicine and senior author. "This is a proof-of-concept study that we hope can one day be applied to human patients."

The current treatment for restoring function when large segments of muscle are injured or removed during tumor surgery is to surgically move a segment of muscle from one part of the body to another. Of course, this reduces function at the donor site.

Several scientific teams are currently working to engineer replacement muscle in the lab by taking small biopsies of muscle tissue, expanding the cells in the lab, and placing them on scaffolds for later implantation. This approach requires a biopsy and the challenge of standardizing the cells.

"Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration," said Lee.

Most tissues in the body contain tissue-specific stem cells that are believed to be the "regenerative machinery" responsible for tissue maintenance. It was these cells, known as satellite or progenitor cells, that the scientists wanted to mobilize.

First, the Wake Forest Baptist scientists investigated whether muscle progenitor cells could be mobilized into an implanted scaffold, which basically serves as a "home" for the cells to grow and develop. Scaffolds were implanted in the lower leg muscle of rats and retrieved for examination after several weeks.

Lab testing revealed that the scaffolds contained muscle satellite cells as well as stem cells that could be differentiated into muscle cells in the lab. In addition, the scaffold had developed a network of blood vessels, with mature vessels forming four weeks after implantation.

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Research in rodents suggests potential for 'in body' muscle regeneration

The medical community has long thought the heart muscle had zero regenerative ability; once it was damaged or otherwise made ineffective, there was no chance of the body making new cells to replace the old ones. That way of thinking is about to change, however, thanks to a new study from Vanderbilt University.

Cardiac stem cells, cells that can create new heart muscle, have been identified inside arteries. The discovery came about as scientists closely examined endothelial cells that line the inner surface of blood vessels. These cells have been known to generate other cells types during mammalian development.

SEE ALSO: Heart attack signs and symptoms in women

People thought that the same heart you had as a young child, you had as an old man or woman as well, said researcher Antonis Hatzopoulos in a press release. Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated.

What Hatzopoulos and his team suggest is that while the body is healthy and the heart is functioning at a normal level, the cardiac stem cells in the arteries maintain the heart muscle, regenerating cells as needed. When illness like coronary artery disease or a medical emergency like a heart attack occur, these stem cells stop making healthy muscle tissue and start making scar tissue instead. This switch can further complicate heart failure by creating another way arteries become blocked.

It looks like the same endothelial system generates myocytes (muscle cells) during homeostasis and then switches to generate scar tissue after a myocardial infarction. After injury, regeneration turns to fibrosis, said Hatzopoulos. If we can understand the molecular mechanisms that regulate the fate switch that happens after injury, perhaps we can use some sort of chemical or drug to restore regeneration and make muscle instead of scar. We think there is an opportunity here to improve the way we treat people who come into the clinic after myocardial infarction (heart attack).

SEE ALSO: Heart attacks increase health issues in partners, spouses

The key in future research will be to uncover why the cardiac stem cells in the arteries switch from making healthy cells to making scar tissue cells. By learning to control this switch, experts may be able to one day encourage the body to make new heart tissue after a heart attack or to combat age and other disease issues.

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Cardiac stem cells have been discovered | Voxxi

Prof Noel Caplice, director of the Centre for Research in Vascular Biology at University College Cork, displays his stent mesh. Photograph: Michael MacSweeney/Provision

As Prof Noel Caplice describes it, a revolutionary new system that avoids putting patients through heart bypass operations was literally a back-of- the-garage effort.

A cardiologist in Cork, he came up with the treatment when working as a cardiologist at the Mayo Clinic seven years ago. During this time, Caplice and an engineer friend worked on prototype meshes and attaching these to stents.

The treatment introduces cells that encourage the body to make new blood vessels that grow past the blockage, actually reversing the disease in as little as three or four weeks.

The treatment may also offer hope for patients suffering from other cardiovascular disorders such as peripheral artery disease, a common risk in diabetes. And, because it uses the patients own cells, there is no question of rejection, says Caplice, director of University College Corks Centre for Research in Vascular Biology.

This would represent a major step forward in the treatment of coronary artery disease, he adds. Instead of open-heart surgery and stitching in arteries to bypass a blockage, it causes the body to grow its own bypass. He is leading the research, which also involves the Mayo Clinic in the US, and the team has published a paper describing the work in the current issue of the journal Biomaterials.

He came up with the idea when working as a cardiologist at the Mayo Clinic seven years ago, he says.

One area we were interested in was patients who were inoperable, patients who were too ill to face open-heart surgery and who had no options. That represents about 20 to 25 per cent of all patients with coronary artery disease.

He was a scientist physician while at the Mayo as he is now, doing research but also working with patients, and he ran his own laboratory. He originally thought of introducing stem cells to encourage blood vessel growth, but when injected they go everywhere, you cant direct them in the body.

Caplice is also a consultant cardiologist at Cork University Hospital.

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Bypassing surgery for new cardiac treatment

Could this experimental treatment reverse damage caused by a heart attack?

The heart muscle relies on a steady flow of oxygen-rich blood to nourish it and keep it pumping. During a heart attack, that blood flow is interrupted by a blockage in an artery. Without blood, the area of heart fed by the affected artery begins to die and scar tissue forms in the area. Over time, this damage can lead to heart failure, especially when one heart attack comes after another.

Though the heart is a tough organ, the damaged portions become unable to pump blood as efficiently as they once could. People who have had a heart attack therefore may face a lifetime of maintenance therapymedications and other treatments aimed at preventing another heart attack and helping the heart work more efficiently.

A new treatment using stem cellswhich have the potential to grow into a variety of heart cell typescould potentially repair and regenerate damaged heart tissue. In a study published last February in The Lancet, researchers treated 17 heart attack patients with an infusion of stem cells taken from their own hearts. A year after the procedure, the amount of scar tissue had shrunk by about 50%.

These results sound dramatic, but are they an indication that we're getting close to perfecting this therapy? "This is a field where, depending on which investigator you ask, you can get incredibly different answers," says Dr. Richard Lee, professor of medicine at Harvard Medical School and a leading expert on stem cell therapy.

"The field is young. Some studies show only modest or no improvement in heart function, but others have shown dramatically improved function," he says. "We're waiting to see if other doctors can also achieve really good results in other patients."

Studies are producing such varied outcomes in part because researchers are taking different approaches to harvesting and using stem cells. Some stem cells are taken from the bone marrow of donors, others from the patient's own heart. It's not clear which approach is the most promising.

Several different types of approaches are being used to repair damaged heart muscle with stem cells. The stem cells, which are often taken from bone marrow, may be inserted into the heart using a catheter. Once in place, stem cells help regenerate damaged heart tissue.

Like any other therapy, injecting stem cells into the heart can fail or cause side effects. If the stem cells are taken from an unrelated donor, the body's immune system may reject them. And if the injected cells can't communicate with the heart's finely tuned electrical system, they may produce dangerous heart rhythms (arrhythmias). So far, side effects haven't been a major issue, though, and that has encouraged investigators to push onward.

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Repairing the heart with stem cells - Harvard Health ...

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue, Vanderbilt University investigators have discovered.

The findings, published recently in Cell Reports, offer insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack.

The heart has long been considered to be an organ without regenerative potential, said Antonis Hatzopoulos, Ph.D., associate professor of Medicine and Cell and Developmental Biology.

"People thought that the same heart you had as a young child, you had as an old man or woman as well," he said.

Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

Hatzopoulos and colleagues postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development.

Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries -- a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

The finding that coronary arteries house a cardiac stem cell "niche" has interesting implications, Hatzopoulos said. Coronary artery disease -- the No. 1 killer in the United States -- would impact this niche.

"Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated," he said.

The current research follows a previous study in which Hatzopoulos and colleagues demonstrated that after a heart attack, endothelial cells give rise to the fibroblasts that generate scar tissue.

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Coronary arteries hold heart-regenerating cells

ROCHESTER, Minn. (KTTC) -- Medical officials are talking about a breakthrough clinical trial that could help the heart repair itself.

On Tuesday afternoon, Mayo Clinic and Cardio3 BioSciences officials outlined an FDA-approved clinical trial to be carried out in the United States. A similar trial has already been underway in Europe.

Cardio3 CEO Christian Homsy said stem cells are a major part of this heart-healing process. "What we do is take cells from a patient and we reprogram those cells to become cardiac reparative cells. Those cells have the ability to come and repair the heart." Those stem cells would come from the bone marrow of patients who suffer from heart failure.

This treatment is the result of a Mayo Clinic discovery. In Mayo's breakthrough process, stem cells that are harvested from a cardiac patient's bone marrow undergo a guided treatment designed to improve heart health in people suffering from heart failure.

Cardio3 officials said a manufacturing facility will be the first thing that is needed for this clinical trial, and the rest of the details like staffing will follow.

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Trial to use stem cells to repair heart

PUBLIC RELEASE DATE:

20-Aug-2014

Contact: Craig Boerner craig.boerner@vanderbilt.edu 615-322-4747 Vanderbilt University Medical Center

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue, Vanderbilt University investigators have discovered.

The findings, published recently in Cell Reports, offer insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack.

The heart has long been considered to be an organ without regenerative potential, said Antonis Hatzopoulos, Ph.D., associate professor of Medicine and Cell and Developmental Biology.

"People thought that the same heart you had as a young child, you had as an old man or woman as well," he said.

Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

Hatzopoulos and colleagues postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development.

Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

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Vanderbilt researchers find that coronary arteries hold heart-regenerating cells

4 hours ago Cells grown on hydrogels of the same stiffness all display fat cell markers and deform the underlying matrix material the same way. Credit: Adam Engler, UC San Diego Jacobs School of Engineering

Bioengineers at the University of California, San Diego have proven that when it comes to guiding stem cells into a specific cell type, the stiffness of the extracellular matrix used to culture them really does matter. When placed in a dish of a very stiff material, or hydrogel, most stem cells become bone-like cells. By comparison, soft materials tend to steer stem cells into soft tissues such as neurons and fat cells. The research team, led by bioengineering professor Adam Engler, also found that a protein binding the stem cell to the hydrogel is not a factor in the differentiation of the stem cell as previously suggested. The protein layer is merely an adhesive, the team reported Aug. 10 in the advance online edition of the journal Nature Materials.

Their findings affirm Engler's prior work on the relationship between matrix stiffness and stem cell differentiations.

"What's remarkable is that you can see that the cells have made the first decisions to become bone cells, with just this one cue. That's why this is important for tissue engineering," said Engler, a professor at the UC San Diego Jacobs School of Engineering.

Engler's team, which includes bioengineering graduate student researchers Ludovic Vincent and Jessica Wen, found that the stem cell differentiation is a response to the mechanical deformation of the hydrogel from the force exerted by the cell. In a series of experiments, the team found that this happens whether the protein tethering the cell to the matrix is tight, loose or nonexistent. To illustrate the concept, Vincent described the pores in the matrix as holes in a sponge covered with ropes of protein fibers. Imagine that a rope is draped over a number of these holes, tethered loosely with only a few anchors or tightly with many anchors. Across multiple samples using a stiff matrix, while varying the degree of tethering, the researchers found no difference in the rate at which stem cells showed signs of turning into bone-like cells. The team also found that the size of the pores in the matrix also had no effect on the differentiation of the stem cells as long as the stiffness of the hydrogel remained the same.

"We made the stiffness the same and changed how the protein is presented to the cells (by varying the size of the pores and tethering) and ask whether or not the cells change their behavior," Vincent said. "Do they respond only to the stiffness? Neither the tethering nor the pore size changed the cells."

"We're only giving them one cue out of dozens that are important in stem cell differentiation," said Engler. "That doesn't mean the other cues are irrelevant; they may still push the cells into a specific cell type. We have just ruled out porosity and tethering, and further emphasized stiffness in this process."

Explore further: Researchers find stem cells remember prior substrates

More information: Interplay of matrix stiffness and protein tethering in stem cell differentiation, Nature Materials, DOI: 10.1038/nmat4051

(Phys.org) A team of researchers working at the University of Colorado has found that human stem cells appear to remember the physical nature of the structure they were grown on, after being moved to a ...

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Matrix stiffness is an essential tool in stem cell differentiation, bioengineers report

Yoshiki Sasai, who was embroiled in a stem-cell scandal, committed suicide He was found with a rope around his neck at science institute Riken in Japan Mr Sasai, 52, was deputy chief of Riken's Center for Developmental Biology He co-authored stem-cell research papers with falsified contents

By Ted Thornhill

Published: 06:20 EST, 5 August 2014 | Updated: 13:25 EST, 5 August 2014

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A senior Japanese scientist embroiled in a stem-cell research scandal died on Tuesday in an apparent suicide, police said.

Yoshiki Sasai, who supervised and co-authored stem-cell research papers that had to be retracted due to falsified contents, was found suffering from cardiac arrest at the government-affiliated science institute Riken in Kobe, in western Japan, according to Hyogo prefectural police.

Sasai, 52, was deputy chief of Riken's Center for Developmental Biology.

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Japanese scientist stem-cell scientist Yoshiki Sasai commits suicide

A Japanese scientist who was among a team of researchers accused of falsifying the results of two stem cell studies committed suicide Tuesday at a government science institute in western Japan. Yoshiki Sasai, deputy director of the Riken Center for Developmental Biology, was found by a security guard at the Kobe facility with a rope around his neck, the Associated Press reports. Authorities said he had suffered from cardiac arrest and was pronounced dead two hours later.

Sasai, 52, was considered an expert in embryonic stem cell research and co-authored two research papers published in January in the journal Nature that detailed a seemingly groundbreaking method of harvesting stem cells to grow new human tissue. Sasai and lead author Haruko Obokata reported having successfully altered ordinary mouse cells into versatile stem cells by immersing them in a mildly acidic solution. The resulting cells were named stimulus-triggered acquisition of pluripotency (STAP) cells.

The studies were initially praised as being on the cutting edge of stem cell treatment, but were quickly disputed when other scientists could not replicate the experimental procedure. The papers were retracted six months later after the journal found they contained erroneous data, among other flaws.

Scientists at RIKEN Center for Developmental Biology in Kobe are deeply concerned about the allegations regarding the recently reported STAP cells, the center said in a statement released in March. We wish to express our strong commitment to maintaining the highest level of scientific integrity to the public and the scientific community. We are fully aware that trust from the society is crucial for research activities carried out in RIKEN.

The scandal apparently affected Sasais health. Following the initial revelation that the research he was involved in may have been flubbed, he was hospitalized in March for stress, according to Riken spokesman Satoru Kagaya, who told reporters during a televised news conference on Tuesday that Sasai "seemed completely exhausted" when they talked over the phone in May.

Several suicide notes were found on Sasais secretarys desk, according to the Wall Street Journal. The content of the notes has not been made public, but officials said two of the notes were addressed to Riken officials, one of whom was Obokata.

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Yoshiki Sasai Suicide: Japanese Stem Cell Scientist Found Dead In Kobe Facility

Abstract

Cardiovascular disease is a major cause of morbidity and mortality throughout the world. Most cardiovascular diseases, such as ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes. Unfortunately, the heart has a limited regenerative capacity and is not able to replace these cardiomyocytes once lost. In recent years, stem cells have been put forward as a potential source for cardiac regeneration. Pre-clinical studies that use stem cell-derived cardiac cells show promising results. The mechanisms, though, are not well understood, results have been variable, sometimes transient in the long term, and often without a mechanistic explanation. There are still several major hurdles to be taken. Stem cell-derived cardiac cells should resemble original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Finally, stem cell therapy needs to be safe, reproducible, and affordable. In this review, we will give an introduction to the principles of stem cell based cardiac repair.

Keywords: Stem cell, Regeneration, Heart, Cardiomyocytes

Repairing the injured body with its own tissue as a substrate has captured human fascination for a long time. In Greek mythology, the Lernaean Hydra was a serpent-like creature with multiple heads that regenerated each time they were cut off and Prometheus, a titan punished by Zeus for stealing fire, had a liver that was able to regenerate each night after it was eaten by an eagle. In 1740, Abraham Tembley discovered that microscopic, freshwater animals had the ability to regenerate their head after amputation, later followed by others who discovered that amphibians have the ability to regenerate their tails, limbs, jaws, and eyes.[1],[2] It took scientists until 1933 before they discovered that some human organs, such as the liver, also have the ability to regenerate.[3]

Regenerative therapies are of major interest in cardiovascular medicine. Most cardiovascular diseases, including ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes and in other diseases, such as sick sinus syndrome, specific cardiac cell properties are missing. Unlike the Lernaean Hydra or the human liver, the heart does not have the ability to regenerate itself spontaneously once damaged. Cardiomyocytes are terminally differentiated and have a limited proliferative capacity. Lost cardiomyocytes are replaced by fibroblasts and connective tissue with the remaining cardiomyocytes becoming hypertrophic, which may eventually lead to heart failure. On the contrary, stem cells proliferate indefinitely and can be directed to differentiate into specialized cell types such as cardiomyocytes. The goal of stem cell-based regenerative medicine in cardiovascular disease, therefore, is to create healthy, functional cardiac cells that are able to integrate in the injured heart and restore its function.

In the past decades, several stem cell types have been discovered. These stem cells can be subdivided based on their differentiation capacity. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are able to differentiate into all three embryonic germ layers, whereas multipotent stem cells can differentiate into a number of closely related cell types of a single embryonic germ layer. Cardiomyocytes were derived from several stem cell sources (). Other types of stem cells do not differentiate into cardiomyocytes themselves, but support cardiac repair by different mechanisms (). In this review, we will refer to all stem cell-derived cardiomyocytes and differentiated cell types enriched for cardiomyocytes as stem cell-derived cardiomyocytes (SCD-CMs), while we will refer to non-cardiomyocyte derivatives (such as vascular cells) as stem cell-derived cardiac support cells (SCD-CSCs).

Summary of stem cells used for cardiac repair.

Characteristics of stem cells studied for cardiac regeneration potential.

In this review, we will give an introduction to the principles of stem cell-based cardiac repair. Our aim is to give a concise up-to date overview of the therapeutic possibilities of stem cells for cardiac injury. First, we describe general requirements for stem cell therapy. After that, we will discuss in more detail the different stem cell sources and their therapeutic effects, since these vary for each cell type.

In order to be suitable for cardiac repair, stem cell-derived cardiac cells should resemble the original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Ideally there would also be beneficial effects on the host myocardium, for example, by stimulating proliferation or differentiation of local progenitors, neovascularization or by inhibiting apoptosis. The minimum requirement for the donor cells is to have no adverse effects. Finally, stem cell therapy needs to be safe, reproducible, and affordable. Each of these requirements will be discussed separately. ()

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Stem cells for cardiac repair: an introduction

here is epidemiological evidence that links type B coxsackie virus (CVB) infection with heart disease, and research published on July 31st in PLOS Pathogens now suggests a mechanism by which early infection impairs the heart's ability to tolerate stress at later stages of life.

CVB infection is very common and affects mostly children. The symptoms range widely: over half of the infections are thought to be asymptomatic, the majority of children who get sick have only a mild fever, and a very small proportion get inflammation of the heart or brain. On the other hand, 70 -- 80% of patients with heart failure show signs of a previous CVB infection but have no history of viral heart disease, raising the possibility that even a mild earlier infection makes them more vulnerable to get heart disease later on.

To investigate this, researchers from San Diego State University, USA, led by Roberta Gottlieb and Ralph Feuer, first established a mouse model of mild juvenile CVB infection. Mice infected with a non-lethal dose of the virus shortly after birth did not develop any heart disease symptoms during the infection or into adulthood, but they had a predisposition to heart disease later in life.

Detailed analysis of the mice after infection showed that the virus does indeed target the heart and is found in cardiac stem cells. When comparing the numbers of cardiac stem cells in previously infected adult mice with uninfected ones, the researchers found significantly smaller numbers in the infected mice.

To test whether the childhood infection and stem cell depletion had any effect on the adult heart, the researchers exposed infected mice to two different types of cardiac stress. They treated some of the mice with a drug known to overstimulate the heart, and they challenged another group by making them swim for 90 minutes every day for 14 days. Following both treatments, the infected mice showed clear signs of early heart disease whereas uninfected controls showed little or no symptoms.

Analyzing the stressed mice in more detail, the researchers found that the hearts from previously infected mice had impaired ability to re-arrange their heart blood vessels and grow new ones. This process, called vascular remodeling, is critical for the heart to respond to changes in the environment, including stress.

As discussed in the article, important open questions remain. For example, does CVB infection affect cardiac stem cells at any age, or is there a vulnerable period in early childhood? It is also not clear whether other strains of CVB have similar properties to the one used here, which was isolated from a patient with heart disease.

Nonetheless, the researchers conclude that their results "support the hypothesis that a mild CVB3 infection early in development can impair the heart's ability to undergo physiologic remodeling, leading to heart disease later in life." They also suggest that "the subtle cardiac alterations might go undetected under normal circumstances but emerge in the setting of increased demand such as intense exercise or chronic high blood pressure."

Story Source:

The above story is based on materials provided by PLOS. Note: Materials may be edited for content and length.

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Childhood coxsackie virus infection depletes cardiac stem cells, might compromise heart health in adults

PUBLIC RELEASE DATE:

31-Jul-2014

Contact: Roberta Gottlieb roberta.gottlieb@cshs.org PLOS

There is epidemiological evidence that links type B coxsackie virus (CVB) infection with heart disease, and research published on July 31st in PLOS Pathogens now suggests a mechanism by which early infection impairs the heart's ability to tolerate stress at later stages of life.

CVB infection is very common and affects mostly children. The symptoms range widely: over half of the infections are thought to be asymptomatic, the majority of children who get sick have only a mild fever, and a very small proportion get inflammation of the heart or brain. On the other hand, 70 80% of patients with heart failure show signs of a previous CVB infection but have no history of viral heart disease, raising the possibility that even a mild earlier infection makes them more vulnerable to get heart disease later on.

To investigate this, researchers from San Diego State University, USA, led by Roberta Gottlieb and Ralph Feuer, first established a mouse model of mild juvenile CVB infection. Mice infected with a non-lethal dose of the virus shortly after birth did not develop any heart disease symptoms during the infection or into adulthood, but they had a predisposition to heart disease later in life.

Detailed analysis of the mice after infection showed that the virus does indeed target the heart and is found in cardiac stem cells. When comparing the numbers of cardiac stem cells in previously infected adult mice with uninfected ones, the researchers found significantly smaller numbers in the infected mice.

To test whether the childhood infection and stem cell depletion had any effect on the adult heart, the researchers exposed infected mice to two different types of cardiac stress. They treated some of the mice with a drug known to overstimulate the heart, and they challenged another group by making them swim for 90 minutes every day for 14 days. Following both treatments, the infected mice showed clear signs of early heart disease whereas uninfected controls showed little or no symptoms.

Analyzing the stressed mice in more detail, the researchers found that the hearts from previously infected mice had impaired ability to re-arrange their heart blood vessels and grow new ones. This process, called vascular remodeling, is critical for the heart to respond to changes in the environment, including stress.

As discussed in the article, important open questions remain. For example, does CVB infection affect cardiac stem cells at any age, or is there a vulnerable period in early childhood? It is also not clear whether other strains of CVB have similar properties to the one used here, which was isolated from a patient with heart disease.

Continue reading here:
Childhood coxsackie virus infection depletes cardiac stem cells and might compromise heart health in adults

The future of medicine is regenerative medicine.

Thats a view shared by Thomas Gonwa, associate director of the Mayo Clinic Center for Regenerative Medicine in Jacksonville, and by Jorge and Leslie Bacardi.

Regenerative medicine will be the cutting-edge medicine of the 21st century, Gonwa says.

We think it is the most important thing happening in medicine, Leslie Bacardi said.

Now the Bacardis, who live in Nassau in the Bahamas, have given what Mayo Clinic officials call a substantial gift to fund ongoing research and clinical trials in regenerative medicine at the Mayo Clinic in Jacksonville.

Jorge Bacardi, part of the family that has been making rum and other spirits for 150 years, declined to specify the amount of the gift. Were not people who boast about the amount we give, he said.

Its an amount that should be sufficient to fund the ongoing research into regenerative medicine in Jacksonville, he said.

Doctors at the Mayo Clinic both in Jacksonville and in Rochester, Minn., now envision a future in which new organs can be grown for patients, using their own cells, and a time when the injection of stem cells can be used to repair a damaged organ.

Last year, Tim Nelson, a physician with the Center for Regenerative Medicine in Rochester, removed tissue from the arm of ABC Nightline reporter Bill Weir and created what Weir called a tiny piece of my cardiac tissue that had dramatically formed into the shape of a heart a pumping, three-dimensional glimpse into a future when this kind of cell could theoretically be injected into a heart-attack victim or a diseased child and literally mend the person from within.

That, to us, was just mind-boggling, Leslie Bacardi said. ... Regenerative medicine is for us an investment in our future and the future of medicine. It may take a while to reap any benefits, but when those benefits do come, it will make the investment seem small.

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Gift from Bacardi family will help Mayo Clinic researchers in Jacksonville close in on 'the future of medicine'

Washington No batteries required: Scientists are creating a biological pacemaker by injecting a gene into the hearts of sick pigs that changed ordinary cardiac cells into a special kind that induces a steady heartbeat.

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans each year.

There are people who desperately need a pacemaker but cant get one safely, said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. This development heralds a new era of gene therapy that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells its about the size of a peppercorn, Marban said that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats per minute or so, more when youre active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For more than a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marbans newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs hearts are so similar to human hearts, Marbans team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs hearts in a spot that doesnt normally initiate heartbeats and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didnt receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

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Scientists working on biological pacemaker

PUBLIC RELEASE DATE:

18-Jul-2014

Contact: Robert Miranda cogcomm@aol.com Cell Transplantation Center of Excellence for Aging and Brain Repair

Putnam Valley, NY. (July 18th 2014) The long-term, positive benefits of transplanted allogenic (other-donated) smooth muscle cells (SMCs) to repair cardiac tissues after myocardial infarction (MI) have been enhanced by the addition of interleukin 10 (IL-10) to the transplanted cells, report researchers in Canada. Their study with rats modeled with MI has shown that SMCs modified with IL-10 - a small, anti-inflammatory protein - benefitted cell survival, improved heart function, and also provided protection against the host's rejection of the allogenic SMCs.

The study will be published in a future issue of Cell Transplantation and is currently freely available on-line as an unedited early e-pub at: http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT1170Dhingra.

Three groups of rats modeled with MI were treated with SMC injections into the MI-damaged area of the heart. One group received unmodified autologous (self-donated) SMCs; a second group received unmodified allogenic (other-donated) SMCs; the third group received allogenic SMCs modified with IL-10. After three weeks, the unmodified autologous cells had engrafted while the unmodified allogenic cells had been rejected by the hosts. However, the IL-10-modified allogenic cells were found to greatly improve cell survival, improve ventricular function, increase myocardial wall thickness, and also prevent host immune response and rejection of the foreign cells.

"While the most appropriate cell type for cardiac repair remains controversial, mesenchymal stem cells (MSCs) that have been differentiated toward myogenic cells restore ventricular function better, as previous studies have shown," said study co-author Ren-Ke Li of the MaRS Centre in Toronto, Canada. "This study demonstrated that IL-10 gene-enhanced cell therapy prevented immune response, increased survival of SMCs in the heart, and improved cardiac function when compared to the results with the control groups."

The researchers noted that while the use of autologous SMCs donated by patients may be optimal for cell therapy, SMCs self-donated by older, debilitated patients who likely have other serious health problems, have limited regenerative capability. Thus, allogenic SMCs from young, healthy donors are the most beneficial cells, but rejection of foreign cells by the host has been a problem in allogenic cell transplantation. This study suggests that the use of allogenic SMCs modified with IL-10 can prevent host rejection.

"Future studies will be required to determine the long-term effects of IL-10 transduced SMCs to evaluate cell survival and cardiac function at six months and one year," concluded the researchers.

"The use of IL-10 overexpression to reduce rejection of allogenic SMCs is an interesting idea" said Dr. Amit N. Patel, director of cardiovascular regenerative medicine at the University of Utah and section editor for Cell Transplantation. "Further studies will help to determine if this manipulation could prove useful for translation of allogenic SMC therapies to humans".

Read more from the original source:
Interleukin-10 aids survival of cells transplanted to repair cardiac tissues after MI

WASHINGTON --

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans a year.

"There are people who desperately need a pacemaker but can't get one safely," said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. "This development heralds a new era of gene therapy" that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells - it's about the size of a peppercorn, Marban says - that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when you're active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For over a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marban's newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs' hearts are so similar to human hearts, Marban's team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs' hearts - in a spot that doesn't normally initiate heartbeats - and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didn't receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

Read the original here:
Scientists using gene therapy to create biological pacemaker

Case Study: Stem Cells vs Coronary Artery Bypass Surgery in a Patient with Multi-Vessel Disease 6 Year Follow Up

Stem cells outperform heart bypass surgery. A heart patient treated with his own stem cells instead of undergoing coronary bypass surgery is exceeding all expectations 6 years after his adult stem cell treatment.

In 2008, Howie Lindeman, then 58 years old, was facing open heart bypass surgery for three blocked coronary arteries. Lindeman, now 64, had his first heart attack at age 39 that severely damaged his heart. He went through multiple procedures over the last several years including having several stents placed in his blocked arteries. When he developed almost constant chest pain and struggled to walk just 25 feet his doctors decided to perform another heart catheterization. They found severe disease; two arteries were 100% blocked and the remaining one was at 80%. Cardiac bypass surgery was immediately recommended.

Lindeman was not quite ready to have his chest cracked open, so he sought alternative options. He was aware of successful treatments for single blocked arteries with stem cells. Determined to avoid surgery he inquired as to the possibility of stem cell treatment for his condition. Dr. Zannos Grekos, a cardiologist with Regenocyte, agreed to treat him as a case study with the understanding that if the treatment was not successful bypass surgery was his only option. Lindeman was treated with his own stem cells in March of 2008. Within one week of the stem cell procedure Lindeman was feeling much better and returned to fulltime work. His subsequent cardiac testing showed continued improvement up to one year later and now 6 years after his procedure he has had no further cardiac events, his heart tests have remained stable and he continues to work fulltime as a sound engineer touring the world.

I have a high stress, high energy job that I absolutely love, says Lindeman. The treatment has allowed me to continue my career and enjoy the active lifestyle I thought I had lost for good. Im a new person and I continue to feel better every day. Click here to see a video of Howie Lindeman.

The Regenocyte treatment is an outpatient procedure and after a period of observation, the patients then are typically discharged from the hospital. The patient is followed up regularly with testing to monitor their progress and measure their results. Lindemans follow up nuclear cardiac stress testing show a greater than 100% improvement in exercise capacity and improved myocardial perfusion. A heart catheterization performed a year after treatment showed a significant increase in heart function and new blood vessels. Lindemans progress was last reported in December 2011.

Dr. Grekos describes how stem cells are extracted from the patient and then processed in a laboratory. The stem cells are then activated and educated to heal the damaged heart. The lab process provides a key step in Regenocytes treatment success, Dr. Grekos explained. The lab extracts the stem cells from the sample and activates them into over a billion cells while educating them to assist the area of the body that needs treatment. These activated stem cells are known as Regenocytes (regenerative cells). The whole process takes about 3 days.

In this ground-breaking treatment, Dr. Zannos Grekos, an interventional cardiologist, inserted a catheter into Lindemans heart. Over the next 20 minutes, adult stem cells were introduced into the damaged part of his heart. The process of tissue repair begins almost immediately.

We continue to see remarkable results from adult stem cell treatment, said Grekos. Successes like those weve seen with Howie are common and show significant promise for diseases in other organs.

Dr. Grekos and the Regenocyte medical team continue to research the impact of adult stem cell therapy on heart disease. For more information on Regenocyte Adult Stem Cell procedures, upcoming seminars, and to see videos featuring Lindeman, visit http://www.regenocyte.com.

Original post:
Case Study: Stem Cells vs Coronary Artery Bypass Surgery in a Patient with Multi-Vessel Disease 6 Year Follow Up

Washington No batteries required: Scientists are creating a biological pacemaker by injecting a gene into the hearts of sick pigs that changed ordinary cardiac cells into a special kind that induces a steady heartbeat.

The study, published Wednesday, is one step toward developing an alternative to electronic pacemakers that are implanted into 300,000 Americans a year.

There are people who desperately need a pacemaker but cant get one safely, said Dr. Eduardo Marban, director of the Cedars-Sinai Heart Institute in Los Angeles, who led the work. This development heralds a new era of gene therapy that one day might offer them an option.

Your heartbeat depends on a natural pacemaker, a small cluster of cells its about the size of a peppercorn, Marban says that generates electrical activity. Called the sinoatrial node, it acts like a metronome to keep the heart pulsing at 60 to 100 beats a minute or so, more when youre active. If that node quits working correctly, hooking the heart to an electronic pacemaker works very well for most people.

But about 2 percent of recipients develop an infection that requires the pacemaker to be removed for weeks until antibiotics wipe out the germs, Marban said. And some fetuses are at risk of stillbirth when their heartbeat falters, a condition called congenital heart block.

For over a decade, teams of researchers have worked to create a biological alternative that might help those kinds of patients, trying such approaches as using stem cells to spur the growth of a new sinoatrial node.

Marbans newest attempt uses gene therapy to reprogram a small number of existing heart muscle cells so that they start looking and acting like natural pacemaker cells instead.

Because pigs hearts are so similar to human hearts, Marbans team studied the approach in 12 laboratory pigs with a defective heart rhythm.

They used a gene named TBX18 that plays a role in the embryonic development of the sinoatrial node. Working through a vein, they injected the gene into some of the pigs hearts in a spot that doesnt normally initiate heartbeats and tracked them for two weeks.

Two days later, treated pigs had faster heartbeats than control pigs who didnt receive the gene, the researchers reported in the journal Science Translational Medicine. That heart rate automatically fluctuated, faster during the day. The treated animals also became more active, without signs of side effects.

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Scientists use gene therapy to create biological pacemaker