Stem cell therapy may help mend a broken heart

Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014

Dilated cardiomyopathy (DCM), a condition where the muscles of the heart are weak and can lead to heart failure, is considered rare in children. However, because the symptoms are not always easy to recognize the condition can go unnoticed for many years, and in severe cases can damage the heart irreparably. In that case the child’s only option is a heart transplant, and a lack of organ donors means that is not always available.

Now, new research out of Japan – published in the journal Science Translation Medicine – could lead the way to new treatments to help children avoid the need for a transplant.

In the study, researchers at Okayama University used heart stem cells called cardiosphere-derived cells (CDCs) to try and repair the damage caused by DCM.  

In a news release, lead researcher Professor Hidemasa Oh, says previous work has shown that because CDCs have the ability to turn into heart tissue they have the potential of reversing damage, but it’s not clear if this would work in children.

“I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children.”

Tests in animal models with DCM showed that the CDCs resulted in a thickening of the heart muscle leading to increased blood flow around the body. This increased blood supply helped repair damaged tissue. Based on this trial the researcher determined what might be a suitable dose of CDCs for children with DCM and were granted permission to carry out a Phase 1 clinical trial.

Five young patients were treated and the results were cautiously encouraging. After a year none of the patients had experienced any severe side effects, but all had indications of improved heart function.

The study also gave the researchers some strong clues as to how the therapy seem to work. They found that when the CDCs were transplanted into the patient they secreted exosomes, which play an important role in cells communicating with one another. These exosomes then helped create a series of actions within the body; they blocked further damage to the heart tissue and they also helped kickstart the repair process.

The Okayama team are now hoping to carry out a Phase 2 clinical trial with more patients. Ultimately, they hope to be able to see if this approach could help prevent the need for a heart transplant in children, and even adults.

Good news for the Tin Man: Pig heart transplants work in baboons for 2+ years

If I only had a heart…

My favorite character in the Wizard of Oz was the Tin Man because of the scene where he cries and starts to rust, causing Dorothy to rush to his aid with an oil can. He is such a tender heap of metal that just needs a heart to be whole. How could you not feel for this sensitive character?

Tin Man, Wizard of Oz

Tin Man, Wizard of Oz

In the end, the Tin Man does get a heart, but it’s actually a heart-shaped clock. Being the nerd that I am, I always wish that he got an actual living heart. And this is where I tie in this tangent to today’s blog. A study came out this week that was able to keep transplanted pig hearts alive in baboons for more than two years – news that would make the Tin Man cry with joy.

The beat goes on from pig to baboon

While this news might sound bizarre, it’s actually a really impressive and important study that could lay down the ground work for transplanting animal organs into humans who desperately need them. Currently over 120,000 people in the US are on on the organ transplant list, and more than 20 people die each day waiting for an organ. For these patients, pig organs, which are similar in size to human organs, might be their temporary life-line while they wait to be matched with a human donor. The study was a collaboration between two teams in the US and Germany and was published in the journal Nature Communications.

As with any organ transplant, the main concern is rejection. Our immune systems are hard-wired to recognize and eliminate foreign agents. That’s why if a patient needs a heart transplant, they can’t receive a heart from just anyone, let alone an animal. They need to find a compatible donor that shares enough genetic similarity so that their immune system doesn’t reject the transplant. But even when patients receive organs from compatible donors, they are forced to take immunosuppressive drugs for the rest of their lives to prevent transplant rejection.

Photo credit (Nick Saltmarsh)

Photo credit (Nick Saltmarsh)

Here’s where this study has made a breakthrough. The teams discovered that they could transplant pig hearts into baboons using a combination of gene therapy and immune-suppressing antibodies. On the gene therapy side, the pigs were genetically altered to lack molecular markers that caused blood clotting in primates. They paired this with antibody treatments that blocked the baboon’s immune system from attacking the pig heart. This combination therapy kept the grafted pig hearts safe and happily functioning for more than 900 days.

Two hearts one baboon

How they transplanted the pig hearts is the really interesting part of this story. The pig heart was hooked up to the baboon’s circulatory system through the abdomen, but they left the baboon’s actual heart so the baboon could function normally while allowing scientists to study the function of the pig heart at the same time. Both hearts and the baboons survived for more than two years, which is longer than their previous benchmarks of 180 (median) and 500 (longest) days.

First author on the study Muhammad Mohiuddin commented on the significance of their study:

Muhammad Mohiuddin

Muhammad Mohiuddin

“It is very significant because it brings us one step closer to using these organs in humans. Xenotransplants—organ transplants between different species—could potentially save thousands of lives each year that are lost due to a shortage of human organs for transplantation.”

 

The next chapter in this story is for the authors to transplant pig hearts into baboons that have their own hearts removed and determine whether their combination therapy is successful in achieving the same results.

Even though much work remains to be done, Mohiuddin shared that he could see pig hearts in humans “in the foreseeable future.”

“In our opinion, this regimen appears potentially safe for human application for patients suffering from end-stage organ failure who might be candidates for initial trials of xenotransplantation.”


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Taking Steps Toward Personalized Heart Transplants

Over five million Americans have heart failure (HF), a condition in which the heart muscles become too weak to pump an adequate amount of blood, oxygen and nutrients to the body’s other organs. People with heart failure suffer from shortness of breath, chronic weakness and a fifty percent chance of dying within the first five years of diagnosis.

SystolicDiastolic_Heartfailure.5518685646fab

Heart failure weakens the heart’s ability to pump blood to the body.
Image credit: Fran Milner, http://www.franimation.com

Heart transplants: swapping one disease for another
The only true cure for heart failure is an organ transplant but donor organs are in limited supply. And those lucky enough to receive a transplant need to take life long immunosuppressive drugs to fight off organ rejection, which often leads to other serious health problems like risk of infection, high blood pressure, diabetes and kidney failure.

It’s not a pretty picture for patients and with a cost to the nation of $32 billion annually, heart failure affects us all.

In a recent Circulation Research journal article, a team at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine (CRM) reported on an incremental yet important step toward an alternative approach to heart transplants: growing bioengineered hearts with a patient’s own stem cells.

Bioengineered hearts: been there, done that
Bioengineered hearts may sound far fetched but eight years have already passed since researchers showed it’s possible with animal models. In that 2008 study, scientists at the University of Minnesota soaked rat hearts in detergents that cleaned away all of the heart cells, leaving behind a scaffold of connective tissue that is secreted by the cells. They then “re-seeded” the scaffold with rat progenitor heart muscle cells. Incredibly, after 4 days in a bioreactor, the tissue began contracting. After 8 days, using electrical stimulation, the hearts could pump with measurable strength.

heartscaffold

Custom built bioreactor with a partially recellularized human whole-heart cardiac scaffold. Image credit: Bernhard Jank, MD, Ott Lab, CRM MGH

Harald Ott, the first author of that proof of concept study, now leads the MGH team in the current study. With an eye toward bringing this method to the clinic, Ott aimed to reproduce the rat studies using human cells and hearts. Specific consent was obtained to recover seventy-three human hearts donated after brain death or cardiac death and were determined to be unusable for clinical transplant.

Just as in the previous study, heart scaffolds were created by clearing away the cells from these organs. Half a billion human heart muscle cells, or cardiomyocytes, that had been grown from human induced pluripotent stem cells (iPS) were then injected into the scaffolds. At this early stage of research, the team did not attempt to reseed the entire heart but specifically focused on areas around the left ventricle – the heart chamber responsible for pumping oxygenated blood out to the rest of the body.

In order to recellularize the scaffold under conditions that resemble the contractions that actually occur in a human heart inside the body, pressure was rhythmically applied using a balloon inside the ventricle – watch it in action by downloading this video.

Screen Shot 2016-03-15 at 9.22.17 AM

Decellularized heart scaffold is injected with iPS heart muscle cells and incubated in a bioreactor to grow new heart muscle (Circ Res. 2016;118:56-72).

After incubating the heart for 14 days in a bioreactor, the team confirmed the cardiomyocytes had formed into functioning heart muscle, or myocardial, tissue that contracted upon electrical stimulation (watch the beating heart by downloading this video).

Looking ahead to a “grow yourself a new heart” future
These results set a course for a future in which scientists could grow a new, personalized heart for people with heart failure. Since the bioengineered heart would be built using iPS cells derived from the patient’s own skin or blood sample, this technique would likely get around the problems of organ rejection and the need for immunosuppressive drugs. Additional analysis in the current study also confirmed that the donor heart scaffold itself, which is void of cells, probably will not pose tissue rejection problems either.

The other key problem, a limited supply of donor hearts, was also addressed. Heart scaffolds donated after cardiac death performed just as well as those donated after brain death which would make this technique available to more patients waiting anxiously for a transplant.

The MGH team would be the first to tell you this “grow yourself a new heart” scenario is still off on the horizon. But as first author, Jacques Guyette, stated in a news release, there are milestones to reach along the way:

“Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial [heart muscle tissue] patch that could replace cardiac tissue damaged due a heart attack or heart failure.”

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