Mending broken hearts

Heart cells derived from human embryonic stem cellsBackground: Pretty much everyone knows that cardiac health is a serious issue. The WHO lists heart disease as the fourth most common killer worldwide, and the CDC puts it at the top for the U.S. When the heart itself doesn’t get enough blood (often due to clogged arteries, aka atherosclerosis), a section of the heart tissue can die – this is what typically happens in a heart attack. The research field would love to come up with a way to replace those dead or damaged cells with new cells, either via cell transplantation or some native source of stem cells, which are cells that can make other cells (scroll to the end for a brief overview of stem cells).

Because many complications can occur with any type of transplant, one example being immune rejection, stimulating the body’s own stem cells to make new heart cells would be ideal. This idea serves as the motivation for this entry’s article.

Title: De novo cardiomyocytes from within the activated adult heart after injury

Authors: Nicola Smart, Sveva Bollini, Karina N. Dubé, Joaquim M. Vieira, Bin Zhou, Sean Davidson, Derek Yellon, Johannes Riegler, Anthony N. Price, Mark F. Lythgoe, William T. Pu & Paul R. Riley

Date of publication: June 8, 2011

Direct link: ttp://www.nature.com/nature/journal/v474/n7353/full/nature10188.html

PMID: 21654746

Abstract: Knowing that there are several limitations to cell transplantation as a means of replacing damaged heart tissue following a heart attack, these researchers set out to try to identify a pool of stem cells in the adult heart that could potentially be utilized to restore damaged heart tissue from within. The authors ultimately found that these adult stem/progenitor cells could be identified by the expression of a gene called Wt1, which was turned on after treating with a peptide (essentially a small version of protein) called thymosin b4. These progenitor cells are suggested to have derived from the epicardium, which is the outer layer of the heart. Stimulating these adult stem cells with thymosin b4 caused them to integrate with damaged heart tissue and become mature cardiomyoctyes (heart muscle cells). Developing a way to utilize these inherent progenitor cells to help mend a damaged heart would be a powerful way to minimize the use of drugs or the need for transplanted tissue.

Methods: The authors made use of mice whose cells would turn green if the Wt1 gene was turned on – recall, the hypothesis is that if Wt1 is turned on in a cell, then that cell may be a heart stem cell. The fact that the cells would turn green when the gene turned on allowed for easier studying of those particular cells later. Mice were injected for 7 days with thymosin b4, because it had previously been shown to improve the function of heart stem cells, before being induced to have a myocardial infarction (heart attack). The researchers induced heart attacks by anesthetizing the mice and then sealing off a major artery of the heart (the left anterior descending artery).  At 2, 4, 7, or 14 days after sealing the artery, the heart was removed and those green progenitor cells could be studied within the heart tissue or isolated from the tissue. Additionally, the authors used some of these isolated stem cells to transplant them into other mice that had had heart attacks, to see if the stem cells could improve the condition of the mice.

Results: Mice pretreated with thymosin b4 before myocardial infarction had significantly more progenitor-like cells in their hearts after myocardial infarction, compared to mice that did not receive these injections. Although mice injected with a negative control did show an increase in progenitor cells following a heart attack, thymosin b4 significantly increased this response. The authors could see that these cells had traveled to the scar on the heart caused by the heart attack, and had started to express some of the genes specific to heart cells – meaning that the stem cells were turning into heart tissue and helping to heal. The progenitor cells isolated from one mouse and transplanted into the heart region of another mouse that had had a heart attack started to turn into heart cells and help to heal the injury in the heart of the recipient mouse as well.

Bottom line: In mice, which are clearly not humans but are the most closely related common lab animal, these researchers identify a pool of cells in the heart with the ability to generate additional heart cells following a heart injury, and this ability is significantly enhanced by the peptide thymosin b4. Although thymosin b4 treatment was not as efficient as an ideal human cell-based therapy would be, the work in this article justifies the search for other molecules that can similarly increase the response of progenitor cells in our hearts to heal and replace the damaged heart tissue that results from heart attacks.

Interesting fact: Working with mice is expensive. Maintaining a mouse cage costs $1-2 per day. Just 30 mouse cages, which this work seemed like it would have needed, at least, would cost $10,950-$21,900 for one year of research. And it is typical for the research in a major publication to represent at least a year’s worth of work, if not four or more.

Stem cells: To make a human, or most any other animal, the first step is sperm meeting egg. The two cells fuse and since each one contains half the genetic information for a whole animal, the fused sperm and egg are considered one cell, called a “zygote.” Obviously an animal is ultimately made up of more than one cell, so the zygote needs to divide to become two cells, then four, then eight, then sixteen, and so on. From that one zygote, there needs to be created a heart, skin, lungs, bone – many kinds of tissues. To get from one cell to many different kinds of cells, many of the early embryonic cells are stem cells or have varying potencies to divide and produce other types of cells (“other types of cells” can include heart cells, fat cells, kidney cells, and even other stem cells). Even as an adult, some of our tissues retain a small population of stem cells so that in the event of injury, for example, damaged tissue can be remade.

 
Smart N, Bollini S, Dubé KN, Vieira JM, Zhou B, Davidson S, Yellon D, Riegler J, Price AN, Lythgoe MF, Pu WT, & Riley PR (2011). De novo cardiomyocytes from within the activated adult heart after injury. Nature, 474 (7353), 640-4 PMID: 21654746

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