Growth Factor Delivery Stimulates Endogenous Heart Repair After Heart Attacks in Pigs


Steven Chamulean and his colleagues at the University Medical Center Utrecht in Holland have examined the use of growth factors to induce healing in the heart after a heart attack. Because simply applying growth factors to the heart will cause them to simply be washed out, Chamulean and his coworkers embedded the growth factors in a material called hydrogel. They were able to measure how long the implanted growth factors lasted. As it turns out, when the growth factors were embedded in the hydrogel, they lasted for four days, and the hydrogel caused the growth factors to spread out into heart tissue with a gradient with the highest concentration at the site of injection (see Bastings, et al., Advanced Healthcare Materials 2013 doi: 10.1002/adhm.201300076).

In his new publication in the Journal of Cardiovascular Translational Research, Chamulean and his group used a new hydrogen called UPy to into which they embedded their growth factors. UPy stands for ureido-pyrimidinone end-capped poly(ethylene glycol) polymer. At the pH of our bodies, UPy hydrogels form a gel-like material made of fibers. When the pH changes, the gel becomes liquid. They embedded the growth factors insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF).

The experimental design of this paper used pigs that were given heart attacks and then reperfused 75 minutes later. One month later, the animals were broken into three groups: just hydrogel, hydrogel with growth factors embedded in it, and growth factors injected into other heart without hydrogel. One month later, the animals were examined for their heart function, and then the animals were sacrificed to examine their heart tissue.

In every case, the hearts treated with only the hydrogel did the poorest of the three groups. The animals injected with gel-less growth factors did better than the controls, but those animals treated with growth factors embedded in UPy hydrogel did the best. The physiological indicators of the hearts from the animals treated with UPy embedded with IGF-1 and HGF improved significantly more than the controls that were treated with only UPy hydrogel. The hearts from animals treated with IGF and HGF without hydrogels improved over controls, by not nearly as well as those treated with growth factor-embedded UPy hydrogels.

When the hearts were examined even more surprises were observed. The animals with hearts that had been treated with UPy + growth factors did not show the enlargement observed in the control hearts. This is significant, because enlargement of the heart is a side effect for a heart attack and is the sign of heart failure. The UPy + growth factor hearts also displayed many signs of dividing cells; far more than hearts from the other two groups. Since the heart has its own resident stem cell population, these growth factors stimulated these stem cells to divide and form new heart muscle, and new blood vessels. Blood vessel density was much higher in the UPy + growth factor group and the pressure against which blood flowed in these hearts was substantially less in this groups, demonstrating that not only was the blood vessel density higher, but blood flow through these vessel networks was much more efficient. There was also plentiful evidence of the formation of new muscle in the UPy + growth factor group. When these hearts were also stained for c-kit, which is a cell surface marker for cardiac stem cells, the UPy + growth factor hearts had lots of them – much more than the other two groups.

This paper reports significant findings because the resident stem cell population in the heart was actively mobilized without having to extract them by means of a biopsy. There is also evidence from Torella and others that IGF-1 and HGF can reactivate the sleeping cardiac stem cells of aged laboratory animals (Circulation Research 2004 94: 514-524). The UP{y hydrogels are well tolerated and are biodegradable. They provide a medium that stays in place and releases embedded growth factors in a sustained manner. The results in this paper provide the rationale to develop growth factor therapy for human patients.

Taiwanese Group Identifies Stem Cell-Based Drug to Rejuvenate Aged Hearts


A southern Taiwan-based National Cheng Kung University research team led by Patrick Ching-Ho Hsieh has discovered that a molecule called prostaglandin E2 can regenerate aged hearts in rodents.

This discovery provides a useful new perspective on heart regeneration and presents an effective option for heart disease patients other than heart transplant.

According to Hsieh, congestive heart disease and other cardiovascular diseases are a leading cause of morbidity and mortality throughout the world. There are some six million patients with congestive heart failure in the US alone and some 400,000 in Taiwan. Despite intensive drug, surgical and other medical interventions, 80 percent of all heart patients die within 8 years of diagnosis.

Even though several experiments and clinical trials have established that heart regeneration can take place, the means by which the heart regenerates is still not completely clear, and there are also no drugs to stimulate heart regeneration by the resident stem cell population in the heart.

Now, after seven years of hard work, Hsieh’s team has identified the critical time period and the essential player that directs heart repair.

Hsieh and his colleagues used genetically engineered mice that Hsieh had developed as a postdoctoral research fellow at Harvard Medical School. By using this transgenic mouse strain, Hsieh and others showed that the self-repair process of the heart begins 7 days after injury and peaks at 10 days after injury.

The “director” of this self-repair process is the molecule PGE2. PGE2 regulates heart-specific stem cell activities.

PGE2

“More importantly, both young and old mice have significant improvements for cardiac remodeling if you treat both of them [with] PGE2,” said Hsieh.

Hsieh’s team also established that PGE2 decreases expression of a gene associated with aging, TGF-beta1. PGE2 also rejuvenates the micro-environment of the aged cells, according to Hsieh.