Archive for the ‘Cardiac Stem Cells’ Category

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

3 hours ago Credit: National Institutes of Health (common fund)

Researchers of the ISREC Institute at the School of Life Sciences, EPFL, have deciphered the mechanism whereby some microRNAs are retained in the cell while others are secreted and delivered to neighboring cells.

There are many ways cells can communicate with each other. One important mode is the release by a cell of signaling molecules that can bind receptors expressed on the surface of another cell to initiate a specific response. In other cases, cells release small vesicles that are packed with signaling molecules of one or more types; such vesicles can fuse with, or be uptaken by, other cells that internalize their content. Exosomes are small vesicles (also called microvesicles) produced by virtually all cell types. After their release to the extracellular environment like the interstices amongst cells, the blood or other body fluids exosomes can fuse with neighboring or distant cells, to which they transfer their cargo of functional molecules. Remarkably, exosomes not only contain conventional signaling molecules like proteins and peptides but also nucleic acids, such as RNAs and DNA fragments, which can horizontally transfer genetic information from one cell to another.

Modulators born within the cells

microRNAs are small RNA molecules that can tune cell behavior by directly modulating the stability of other RNA molecules, called messenger RNAs (mRNAs), which are the precursors of all cellular proteins. Several dozen functional microRNA species are produced by each cell type. These may target hundreds of mRNAs to finely modulate the global protein output of the cell. Recent studies have shown that microRNAs are packed, along with other molecules, into exosomes and are secreted to the extracellular environment by many distinct cell types. This discovery suggests a new mechanism of cell communication involving the ability of exosomal microRNAs to "reprogram" the gene expression of cells that have internalized them. For example, some of the internalized microRNAs could influence the cell's ability to produce certain proteins that, in turn, may affect the cell functions and behavior.

Sorting out microRNAs

Interestingly, the microRNA composition of exosomes may differ from that of the producer cell. Indeed, some microRNA species can be abundant in the cell but scarce in its exosomes, and vice versa. This finding suggests that the sorting of specific microRNAs to exosomes may be actively regulated, although the underlying mechanisms have remained elusive. With the financial support of the Fonds National Suisse de la Recherche Scientifique (SNSF), Michele De Palma and his colleagues at EPFL and at the Swiss Institute of Bioinformatics (SIB) of the University of Lausanne, have now identified a mechanism that may explain the differential incorporation of microRNAs into exosomes. By performing RNA sequencing and bioinformatic modeling of the data, the researchers found that the sorting of microRNAs to exosomes is directly controlled by the abundance of the mRNAs they target in the producer cell. When the target mRNAs of a given microRNA increase in the cell for example as a consequence of cell activation the microRNA is more likely to be retained in the cell and excluded from exosomes. Conversely, if the mRNA levels decline, the microRNA is loaded into exosomes and secreted. These findings imply that the secretion of microRNAs through exosomes is a mechanism whereby cells rapidly dispose the microRNAs that are in excess of their target mRNAs.

"It may seem a quite intuitive and straightforward mechanism," explains Mario Leonardo Squadrito, a leading author of the study, "but investigating the cross-talk between microRNAs and their targeted transcripts has proven challenging and required complex bioinformatic analyses." The authors also took advantage of lentiviral vectors they had developed to specifically introduce or delete selected microRNAs, or their targeted mRNAs, in the cells. "These experiments have been crucial to document how microRNAs can dynamically traffic from the cell cytoplasm to exosomes, in response to changes of the RNA levels," adds Squadrito.

Biological markers

The microRNAs contained in circulating exosomes ("microRNA signatures") are increasingly recognized as potential biomarkers of disease and response to therapy. The findings of De Palma and colleagues not only identify a general mechanism regulating microRNA sorting to exosomes, but may also help understand how the microRNA signatures observed in circulating exosomes originate from within the cells. For example, patients with some types of cancer display specific microRNA signatures in their blood that may reflect the altered, and possibly evolving, mRNA (and protein) expression profiles of their tumors. Another important area of research is the analysis of the fate of the microRNAs once the exosomes are internalized by cells. "Although our findings suggest that a significant proportion of the internalized microRNAs may be degraded, we employed sensitive new techniques to demonstrate that they retain the ability to modulate gene expression in the target cell," explains Caroline Baer, another leading author of the study. "A fascinating side of the story is that cells produce profuse amounts of exosomes packed with microRNAs. If cells of different type and origin can effectively exchange this form of genetic information, their boundaries must be less tight than we used to think."

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A better understanding of cell to cell communication

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

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

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Newswise LOS ANGELES (Aug. 12, 2014) Regenerative medicine experts at the Cedars-Sinai Heart Institute have opened a new clinic to evaluate heart and vascular disease patients for participation in stem cell medical studies.

Led by Eduardo Marbn, MD, PhD, director of the Cedars-Sinai Heart Institute, and Timothy Henry, MD, director of the Heart Institutes Cardiology Division, the doctors and researchers at the Cedars-Sinai Heart Institute Regenerative Medicine Clinic use a scientific approach to assess the possible benefits of stem cells to repair damaged or diseased cardiovascular tissues. The clinic is believed to be the first at a major U.S. academic medical center dedicated to matching patients with appropriate stem cell clinical trials, whether those research interventions are available at the medical center or at other institutions.

The Heart Institute Regenerative Medicine Clinic offers consultative services for patients with heart and vascular disease who may qualify for investigative stem cell therapy. The goal is to provide research options to patients who remain symptomatic on their current management regimen, or for patients with stable heart disease who are concerned about disease progression.

Over the past decade, medical experts have predicted that in the future, stem cell therapies would transform heart disease treatment and save lives, said Shlomo Melmed, MD, dean of the Cedars-Sinai faculty and the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine. At Cedars-Sinai, we have a track record of successfully directing cardiac stem cell studies as well as transferring innovations from the laboratory to the patient bedside.

In 2009, Marbn and his team completed the worlds first procedure in which a patients own heart tissue was used to grow specialized heart stem cells. The specialized cells were then injected back into the patients heart in an effort to repair and re-grow 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 stem cell treatment, heart attack patients demonstrated a significant reduction in the size of the scar left on the heart muscle after a heart attack.

Henry has served as principal investigator of multiple large, multicenter trials in acute coronary syndromes, myocardial infarction and angiogenesis, including several ongoing cardiovascular stem cell trials. He also is principal investigator for one of seven NIH Clinical Cardiovascular Stem Cell Centers.

Our goal is to help make stem cells a regular treatment option for heart disease, Henry said. Right now, many patients with advanced heart disease have limited treatment options. Stem cells offer not only hope but a real chance of a game-changing treatment.

As part of each patients assessment in the Heart Regenerative Medicine Clinic, physicians will evaluate patients interested in participating in stem cell clinical trials at Cedars-Sinai and, for patients willing to travel at other medical institutions across the nation. For patients willing to travel to participate in research, Cedars-Sinai physicians will work closely with investigators at other centers to expedite referrals and seamlessly transfer all relevant medical records.

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Cedars-Sinai Heart Institute Opens First-of-its-Kind Research Stem Cell Clinic for Cardiac Patients

11 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

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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Tragic:Yoshiki Sasai, who was embroiled in a stem-cell scandal, committed suicide and was found with a rope around his neck at his place of work

A security guard found him with a rope around his neck, according to Riken. Sasai was rushed to a hospital, but was pronounced dead two hours later.

Police and Riken said Sasai left what appeared to be suicide notes, but refused to disclose their contents.

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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

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."

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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

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

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.

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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".

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Interleukin-10 aids survival of cells transplanted to repair cardiac tissues after MI

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.

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

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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.

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Scientists creating a biological pacemaker

By LAURAN NEERGAARD AP Medical Writer

WASHINGTON (AP) - 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 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.

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Trying gene therapy to create biological pacemaker - Quincy Herald-Whig | Illinois & Missouri News, Sports

Council of Scientific and Industrial Research (CSIR) Centre for Cellular and Molecular Biology (CCMB) Director, Dr Ch. Mohan Rao today claimed that the heart disease can be treated without surgeries in future.

Addressing after inaugurating the 19th Annual conference of the Cardiological Society of India (CSI-AP Chapter) here, Dr Rao said that in the recent research in molecular biology found that 'heart' too have 'stem cells' which will help to automatically build the damaged part of any organ.

He said that further research also going with collaboration of other foreign institutions on how to bring the 'stem cells' out and repair.

Once the solution is found, the cardiac diseases can be healed with surgery, Dr Rao said.

''This development will make the stem cell based therapy replace the chemical based therapy in Cardiology,'' he added.

Irregular eating habits and busy lifestyle are among the major causes of the cordial illness, he said and advised to the youth to follow healthy lifestyle to avoid heart related problems.

While talking about the latest research, he said, ''To reduce the deaths due to cardiac illness the CCMB is working along with the scientists from Japan, the US and Italy to develop the an easier way to treatment.''

Dr Rao also given a clarion call to Cardiology experts to come forward for joint research on cardiac problems.

Encouraging the research in Cardiology, Dr Rao also invited the young medicos to visit the CCMB campus and work with the institute.

Discussing various kinds of heart diseases, he said, ''Dilated Cardiomyopathy is one of the most common heart disease among the children.''

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Cardiac diseases to be treated without surgeries soon as stem cells found

By Ben Spencer

Published: 09:48 EST, 4 July 2014 | Updated: 10:20 EST, 4 July 2014

Fat removed from a heart attack patient during cardiac surgery could be re-injected into their chest to lower the risk of repeat problems, research suggests.

Scientists think that stem cells in fatty tissue could be extracted and inserted directly into the heart, reducing the chance of future attacks.

The stem cells - blank cells capable of acting as a repair kit for the body by replacing worn-out tissue - can improve the functioning of the heart and strengthen crucial arteries and veins, the researchers found.

Usually most of the fat that is found during open heart surgery is removed and then discarded.

Scientists believe fat removed from a heart attack patient during cardiac surgery could be re-injected into their chest to lower the risk of repeat problems. Stock image

But the new study suggests that the fat could be retained and the useful stem cells isolated and injected back into the heart - all while the patient is still on the operating table.

Canadian cardiologist Dr Ganghong Tian, who will present his findings at a European Society of Cardiology conference in Barcelona tomorrow (Sunday), said: During cardiac surgery fat tissue may need to be removed from patients to expose the heart.

We were intrigued to find out whether this mediastinal fat, which would otherwise be discarded, contained stem cells that could be injected back into the heart before closing the chest.

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Fat cells removed from heart attack patients could be re-injected into their chest to help repair the organ ...

By Jim Kasuba The News-Herald Twitter: @JKasuba

Elizabeth Disney (left) turned out to be a suitable blood stem donor for her sister, Brittany, who is afflicted with Burkitt lymphoma, considered to be an extremely rare disease for a young woman of only 23. Photo courtesy of Donna Smith

RIVERVIEW Battling a rare cancer has been a rough road for Brittany Disney, but the worst may be behind her.

The good news is that a suitable stem cell donor has been found and the transplant surgery went well. The not-so-good news is that theres a long recovery period and shes still in a lot of pain.

Donna Smith, a close friend of the family, said the young woman underwent stem cell replacement on June 6.

There was a one in four chance that a sibling would be a match, Smith said. (Her sister) Elizabeth had five out of six markers to be a stem cell donor for her.

Disney, 23, was diagnosed late last year with stage four Burkitt lymphoma, a form of non-Hodgkins lymphoma in which cancer starts in immune cells called B-cells. Recognized as the fastest growing human tumor, Burkitt lymphoma is associated with impaired immunity and is rapidly fatal if left untreated.

Burkitt lymphoma is so rare in young adult women that the Henry Ford Health System wrote about the case in a medical journal, said one of Disneys college friends.

In November, friends and family sponsored a spaghetti dinner fundraiser to assist the family with medical bills and expenses, but things continued to look bleak, as a stem cell transplant appeared to be the only answer to treating the condition.

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Riverview woman recovers from stem cell transplant; family seeking notes of encouragement

San Francisco, California (PRWEB) June 19, 2014

The global market for artificial organ and bionics is expected to reach USD 38.75 billion by 2020 at an estimated CAGR of 9.3% from 2014 to 2020, according to a new study by Grand View Research, Inc. Increasing prevalence of acute renal failure and renal disorders due to lifestyle habits such as excessive alcohol consumption and growing geriatric population base causing a rise in organ failure rates is expected to serve this market as a high impact rendering driver. In addition, growing incidence rates of accidents is expected to boost the demand for organ transplants, thus increasing demand for artificial organ. Artificial kidney dominated the global market in 2013, with revenue estimated at over USD 12.21 billion; demand is expected grow due to the increasing chronic kidney patients. Artificial liver is the fastest growing market segment, at an estimated CAGR of 11.0% from 2014 to 2020.

The report Artificial Organ And Bionics Market Analysis By Product (Artificial Heart, Liver, Kidney, Pancreas, Bionic, Limbs, Heart Valves, Cardiac, Vision), By Technology (Mechanical, Electronic) And Segment Forecasts To 2020, is available now to Grand View Research customers at http://www.grandviewresearch.com/industry-analysis/artificial-organ-and-bionics

Request free sample of this report @ http://www.grandviewresearch.com/industry-analysis/artificial-organ-and-bionics/request.

Further key findings from the study suggest:

Browse all reports of this category @ http://www.grandviewresearch.com/industry/healthcare-it.

For the purpose of this study, Grand View Research has segmented the global artificial organ and bionics market on the basis of product, technology and region:

Browse all Grand View research upcoming reports @ http://www.grandviewresearch.com/ongoing-reports.

Latest Reports by Grand View Research:

Phytosterols Market Analysis By Application (Pharmaceutical, Cosmetics, Food Ingredients), By Product (Beta-Sitosterol, Campesterol, Stigmasterol, Ergosterol) And Segment Forecasts To 2020 (http://www.grandviewresearch.com/industry-analysis/phytosterols-market)

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Artificial Organ & Bionics Market by Product (Artificial Heart, Liver, Kidney, Cardiac), by Technology (Mechanical ...

WASHINGTON Scientists have come up with a bright idea to repair teeth And they say their concept using laser light to entice the bodys own stem cells into action may offer enormous promise beyond just dentistry in the field of regenerative medicine.

The researchers used a low-power laser to coax dental stem cells to form dentin, the hard tissue that makes up most of a tooth, in studies involving rats and mice and using human cells in a laboratory. The study appeared in the journal Science Translational Medicine.

They did not regenerate an entire tooth in part because the enamel part was too tricky. But merely getting dentin to grow could help alleviate the need for root canal treatment, the painful procedure to remove dead or dying nerve tissue and bacteria from inside a tooth, they said.

Im a dentist by training. So I think it has potential for great impact in clinical dentistry, researcher Praveen Arany of the National Institute of Dental and Craniofacial Research, part of the U.S. National Institutes of Health, said Friday. Arany expressed hope that human clinical trials could get approval in the near future.

Our treatment modality does not introduce anything new to the body, and lasers are routinely used in medicine and dentistry, so the barriers to clinical translation are low, added Harvard University bioengineering professor David Mooney. It would be a substantial advance in the field if we can regenerate teeth rather than replace them.

Using existing regeneration methods, scientists must take stem cells from the body, manipulate them in a lab and put them back into the body. This new technique stimulates action in stem cells that are already in place.

Scientists had long noticed that low-level laser therapy can stimulate biological processes like rejuvenating skin and stimulating hair growth but were not sure of the mechanisms. Arany noted the importance of finding the right laser dose, saying: Too low doesnt work and too high causes damage.

The researchers found that laser exposure of the tooth at the right intensity prompted certain oxygen-containing molecules to activate a cell protein that is known to be involved in development, healing and immune functions.

This protein in turn directed stem cells present in tooth pulp to turn into dentin. Stem cells are master cells that are capable of transforming into various types of tissues in the body.

The question is whether using this method could get other stem cells to become useful in laser-induced regenerative medicine. Arany said he is hopeful it can be used in healing wounds, regenerating cardiac tissue, dealing with inflammation issues and fixing bone damage, among other applications.

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Washington, May 12 : Researchers have merged stem cell and 'organ-on-a-chip' technologies to grow, for the first time, functioning human heart tissue carrying an inherited cardiovascular disease.

The research appears to be a big step forward for personalized medicine, as it is working proof that a chunk of tissue containing a patient's specific genetic disorder can be replicated in the laboratory.

Using their interdisciplinary approach, the investigators modeled the cardiovascular disease Barth syndrome, a rare X-linked cardiac disorder caused by mutation of a single gene called Tafazzin, or TAZ. The disorder, which is currently untreatable, primarily appears in boys, and is associated with a number of symptoms affecting heart and skeletal muscle function.

The researchers took skin cells from two Barth syndrome patients, and manipulated the cells to become stem cells that carried these patients' TAZ mutations. Instead of using the stem cells to generate single heart cells in a dish, the cells were grown on chips lined with human extracellular matrix proteins that mimic their natural environment, tricking the cells into joining together as they would if they were forming a diseased human heart.

The engineered diseased tissue contracted very weakly, as would the heart muscle seen in Barth syndrome patients.

The investigators then used genome editinga technique pioneered by Harvard collaborator George Church, PhDto mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue.

On the other hand, delivering the TAZ gene product to diseased tissue in the laboratory corrected the contractile defect, creating the first tissue-based model of correction of a genetic heart disease.

Furthermore, the scientists discovered that the TAZ mutation works in such a way to disrupt the normal activity of mitochondria, often called the power plants of the cell for their role in making energy.

However, the mutation didn't seem to affect overall energy supply of the cells. In what could be a newly identified function for mitochondria, the researchers describe a direct link between mitochondrial function and a heart cell's ability to build itself in a way that allows it to contract.

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Stem cell and 'organ-on-a-chip' merger step forward for personalized meds

PUBLIC RELEASE DATE:

11-May-2014

Contact: Joseph Caputo joseph_caputo@harvard.edu 617-496-1491 Harvard University

Cambridge, MAHarvard scientists have merged stem cell and 'organ-on-a-chip' technologies to grow, for the first time, functioning human heart tissue carrying an inherited cardiovascular disease. The research appears to be a big step forward for personalized medicine, as it is working proof that a chunk of tissue containing a patient's specific genetic disorder can be replicated in the laboratory.

The work, published in Nature Medicine, is the result of a collaborative effort bringing together scientists from the Harvard Stem Cell Institute, the Wyss Institute for Biologically Inspired Engineering, Boston Children's Hospital, the Harvard School of Engineering and Applied Sciences, and Harvard Medical School. It combines the 'organs-on-chips' expertise of Kevin Kit Parker, PhD, and stem cell and clinical insights by William Pu, MD.

Using their interdisciplinary approach, the investigators modeled the cardiovascular disease Barth syndrome, a rare X-linked cardiac disorder caused by mutation of a single gene called Tafazzin, or TAZ. The disorder, which is currently untreatable, primarily appears in boys, and is associated with a number of symptoms affecting heart and skeletal muscle function.

The researchers took skin cells from two Barth syndrome patients, and manipulated the cells to become stem cells that carried these patients' TAZ mutations. Instead of using the stem cells to generate single heart cells in a dish, the cells were grown on chips lined with human extracellular matrix proteins that mimic their natural environment, tricking the cells into joining together as they would if they were forming a diseased human heart. The engineered diseased tissue contracted very weakly, as would the heart muscle seen in Barth syndrome patients.

The investigators then used genome editinga technique pioneered by Harvard collaborator George Church, PhDto mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue. On the other hand, delivering the TAZ gene product to diseased tissue in the laboratory corrected the contractile defect, creating the first tissue-based model of correction of a genetic heart disease.

"You don't really understand the meaning of a single cell's genetic mutation until you build a huge chunk of organ and see how it functions or doesn't function," said Parker, who has spent over a decade working on 'organs-on-chips' technology. "In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly. Being able to model the disease from a single cell all the way up to heart tissue, I think that's a big advance."

Furthermore, the scientists discovered that the TAZ mutation works in such a way to disrupt the normal activity of mitochondria, often called the power plants of the cell for their role in making energy. However, the mutation didn't seem to affect overall energy supply of the cells. In what could be a newly identified function for mitochondria, the researchers describe a direct link between mitochondrial function and a heart cell's ability to build itself in a way that allows it to contract.

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Patient stem cells used to make 'heart disease-on-a-chip'

The entire heart muscle in young children may hold untapped potential for regeneration, new research suggests.

For decades, scientists believed that after a child's first few days of life, cardiac muscle cells did not divide. Instead, the assumption was that the heart could only grow by having the muscle cells become larger.

Cracks were already appearing in that theory. But new findings in mice, scheduled for publication in Cell, provide a dramatic counterexample -- with implications for the treatment of congenital heart disorders in humans.

Researchers at Emory University School of Medicine have discovered that in young mice 15 days old, cardiac muscle cells undergo a precisely timed spurt of cell division lasting around a day. The total number of cardiac muscle cells increases by about 40 percent during this time, when the rest of the body is growing rapidly. [A 15-day-old mouse is roughly comparable to a child in kindergarten; puberty occurs at day 30-35 in mice.]

The burst of cell division is driven by a surge of thyroid hormone, the researchers found. This suggests that thyroid hormone could aid in the treatment of children with congenital heart defects. In fact, doctors have already tested thyroid hormone supplementation in this setting on a small scale.

The findings also have broader hints for researchers developing therapies for the heart. Activating the regenerative potential of the muscle cells themselves is a strategy that is an alternative to focusing on the heart's stem cells, says senior author Ahsan Husain, PhD, professor of medicine (cardiology) at Emory University School of Medicine.

"It's not as dramatic as in fish or amphibians, but we can show that in young mice, the entire heart is capable of regeneration, not just the stem cells," he says.

The Emory researchers collaborated with Robert Graham, MD, executive director of the Victor Change Cardiac Research Institute in Australia. Co-first authors of the paper are Nawazish Naqvi, PhD, assistant professor of medicine at Emory and Ming Li, PhD, at Victor Chang.

The researchers tested how much mice, at the age of day 15, can recover from the blockage of a coronary artery. Consistent with previous research, newborn (day 2) mice showed a high level of repair after such an injury, but at day 21, they did not. The day 15 mice recovered more than the day 21 mice, indicating that some repair is still possible at day 15.

The discovery came unexpectedly during the course of Naqvi and Husain's investigation of the role of the gene c-kit -- an important marker for stem cells -- in cardiac muscle growth. Adult mice with a disabled c-kit gene in the heart have more cardiac muscle cells. The researchers wanted to know: when does this difference appear?

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Spurt of heart muscle cell division seen in mice well after birth: Implications for repair of congenital heart defects