Can Hearts Heal Themselves?

By Malika Ramani, '21

The average human heart pumps 100,000 times per day. [1] In doing so, it circulates 2,000 gallons of blood throughout an intricate network of vessels that distribute it to various organs and back to the heart, which requires a constant supply of oxygen and nutrients in order to function. Over time, however, cholesterol and fatty deposits can build up in the vessels leading to the heart – the coronary arteries – impeding blood flow. [2] If an artery becomes entirely blocked and blood flow to the heart is fully restricted, permanent damage and death of heart muscle tissue (known as “myocardium”) occurs: a heart attack. 
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Scar tissue then forms over the damaged area, impairing the heart’s ability to contract and pump effectively. Scientists have spent years exploring methods by which to counteract the long-lasting consequences of this tissue death, posing a game-changing question: can hearts regenerate their myocardium via stem cells after damage has occurred?

But when it comes to this potential regenerative ability, the jury is still undecided; disputes regarding whether adult cardiac stem cells – which might have the power to repair damaged myocardium – even exist are ongoing. The debate first arose in the early 2000s, when multiple teams of researchers reported that bone marrow-derived cells that expressed the protein c-Kit+ could generate new muscle tissue if injected into rodents’ damaged myocardium. 

An April 2018 article published by Li et al. in Circulation, however, refutes the claims made by these previous studies. The authors instead put forth “undeniable evidence” that progenitor cells (stem cells that can differentiate into several types of specialized cells) do not truly have the ability to generate new cardiac muscle cells (known as “cardiomyocytes”) at the site of injury in heart muscle. [3]

Jeffery Molkentin, a cardiovascular biologist at Cincinnati Children’s Hospital, is among the researchers who contributed to these recent findings. According to him, the human heart cannot regenerate itself after its tissue dies, and in 2014, he and his colleagues published a study reporting that c-Kit+ cells in adult mouse tissue almost never produce new cardiomyocytes. In 2018, however, a research team from the Magna Graecia University in Italy responded to Molkentin’s publication by identifying certain “flaws” in his technique for tracing cell lineage. According to scientists Bernardo Nadal-Ginard and Daniele Torella, Molkentin’s method of fluorescently tagging cells that express c-Kit+ compromised the gene these cells require for c-Kit+ expression and thus diminished the progenitor cells’ ability to regenerate tissue.

To circumvent this, the 2018 Circulationstudy instead fluorescently labeled nonmyocytes and newly generated muscle cells (instead of labeling the stem cells) in order to distinguish these cells from existing cardiomyocytes. The researchers chose this particular process in order to address whether any stem cells at all exist in the adult mouse heart. The results of this experiment revealed that although stem cells do indeed generate cardiomyocytes in embryonic hearts, this same effect was not replicated in the adult rodent heart (during both a resting state and after a heart attack). [4]

Despite these disheartening results, many researchers are still optimistic about the regenerative potential of cardiac stem cells. For example, Stanford University cardiologist Phillip Yang argues that it might not even be necessary for stem cells to differentiate into cardiomyocytes in order to repair damaged heart tissue. Yang claims it is “incontrovertible” that stem cells improve heart function in mouse injury models, and he supplants current theories about myocyte regeneration with a new hypothesis: that progenitor cells secrete small molecules known as “paracrine factors” that stimulate heart tissue repair. [5]
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These contradictory studies indicate that researchers still do not fully understand the function of progenitor cells in both mouse and human injury models. Given, however, the worldwide prevalence of cardiovascular disease, it is clear that further investigation into these cells is warranted. Both research and time will tell if cardiac stem cells can indeed offer healing abilities to the one million Americans who experience a new or recurrent heart attack every year. [6]

Works Cited:

[1] Beckerman J. How Your Heart Works [Internet]. WebMD. 2017 [cited 2018 Oct 21]. Available from: https://www.webmd.com/hypertension-high-blood-pressure/hypertension-working-heart#1.
 
[2] Heart Attack (Myocardial Infarction) [Internet]. Cleveland Clinic. 2017 [cited 2018 Oct 21]. Available from: https://my.clevelandclinic.org/health/diseases/16818-heart-attack-myocardial-infarction.
 
[3] Kwon D. Adult Cardiac Stem Cells Don't Exist: Study [Internet]. The Scientist Magazine. 2018 [cited 2018 Oct 21]. Available from: https://www.the-scientist.com/news-opinion/adult-cardiac-stem-cells-dont-exist--study-64752.
 
[4] Li Y, He L, Huang X, Bhaloo SI, Zhao H, Zhang S, et al. Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases. Circulation [Internet]. 2018 Apr 26 [cited 2018 Oct 21]; 138(8):793–805. Available from: https://www.ahajournals.org/doi/10.1161/ CIRCULATIONAHA.118.034250.
 
[5] Grens K. Mysterious Mechanisms of Cardiac Cell Therapy [Internet]. The Scientist Magazine. 2016 [cited 2018 Oct 21]. Available from: https://the-scientist.com/daily-news/mysterious-mechanisms-of-cardiac-cell-therapy-34078.
 
[6] Rubenfire M. Heart Disease and Stroke Statistics-2018 Update [Internet]. American College of Cardiology. 2018 [cited 2018 Oct 21]. Available from: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/02/09/11/59/heart-disease-and-stroke-statistics-2018-update.