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Monday, 27 July 2015

Can we regenerate our hearts?

In ancient Egypt the heart was a revered organ; it was believed to be the source of the soul. According to the Egyptians, all of our emotions, wisdom and even personality traits were thought to originate in the heart. It was one of the few things left inside a body for mummification, whilst the brain - whose only purpose was thought to be the provider of nasal mucus, or a ‘runny nose’ - was simply thrown away. Though we still agree with the vital role the heart plays in life, after more than 5,000 years of study the organ is now generally considered to be well understood. That being said, some scientists believe that the full potential of our heart has not yet been reached. This article aims to explore one of the questions currently being posed by researchers: could our heart regenerate itself?

Left Ventricular Assist Device (LVAD)
Currently, a failing heart requires surgical assistance, such as the installation of a Ventricular Assist Device. Cardioregeneration could make such devices unnecessary. Image by Blausen Medical Communications, Inc. [CC BY 3.0], via Wikimedia Commons


The phenomenal organ comes in all shapes and sizes. A blue whale's heart is gigantic; it weighs over 680 kilograms, more than the combined weight of two adult male grizzly bears. An average human heart weighs less than 500 grams. But beating more than 100,000 times a day, our cardiac muscle still pumps a considerable 12 pints of blood around the body every minute. As mammals, humans have a two-circuit circulatory system. Our muscles (including the heart) need oxygen to function, and produce carbon dioxide from it. The blood is responsible for transporting these gases around the body. This oxygen supply is crucial; if you have a heart attack, caused by blockages in the circulatory system called blood clots, blood (and therefore oxygen) stops flowing to the heart and can stop it beating… sometimes permanently.

Cardiomyocytes

All muscles are made up of cells called myocytes; long tubes that produce electrical impulses. If they don’t receive enough oxygen they die. When an electrical signal is created the myocytes contract, making the muscle move, which enables our hearts to beat. If the oxygen supply stops and enough cells die, contraction ceases - catastrophic for the heart. When cardiomyocytes are damaged or die, in humans that is the end of them. However, in some animals regeneration is possible; zebrafish for example can completely regrow up to a fifth of their hearts. The difference lies in how the cardiomyocytes develop.

let-7 microRNA progressing cardiomyocyte development
Three stages of cardiomyocyte development with their nuclei, the cell information center, stained blue. In green are the filaments that contract when the myocyte receives an electrical signal. The combined contraction of the cardiomyocytes creates our heartbeat! Image credit: PNAS

When cardiomyocytes are first made, they proliferate to build the heart. At this early stage of the cell cycle they are in a ‘primitive’ state, characterized by an ability for rapid division but poor contractile force. Once the heart is an active muscle the cardiomyocytes mature. The regenerative capabilities of these advanced myocytes are widely debated by scientists, but it is agreed they produce much stronger contractions. Despite being a lot smaller than the blue whales’, our hearts and bodies are quite large when compared to those of animals that can regenerate. For zebrafish, salamanders and tadpoles the weak contractions of the primitive cardiomyocytes are enough to sustain them. Conversely, to maintain a healthy blood pressure and circulation throughout our body we need stronger heart beats. This means that we have to keep our more efficient but potentially less regenerative cardiomyocytes throughout our lives, as our hearts would fail if they were made of the weaker immature ones.

Though it is agreed that we have the capacity to produce new cardiomyocytes, researchers are unsure of the exact extent to which human heart cells can be regenerated - varying from 1-40%. However another missing piece of the puzzle is where they come from. When the heart is first being formed, they are produced by progenitor cells, which are made from stem cells. These, as the name suggest, are what all the cells in our body stem from. Hypotheses on human heart regeneration are divided by two main ideas; either progenitor cells continue to produce and replace the cardiomyocytes, or the mature cells arise through cell division of existing myocytes. Though there is an emerging consensus that the latter is the main source, the progenitors (through stem cell research) do have evidence supporting their contribution to regeneration.

Multi- and Pluripotent Stem Cells

Different animals use various types of stem cells for cardioregeneration; multipotent and pluripotent. You could think of the two variations as different key cards in a hotel. A multipotent key card would be given to a guest and it will open one door in the hotel, so a different key card is needed for every door. A pluripotent key card though, or a ‘master’ key, held by the hotel manager could open every door. Multipotent stem cells can only make one tissue type each. Salamanders (for example) can regrow entire limbs through a combination of these muscle, nerve and other tissue specific stem cells. Pluripotent stem cells on the other hand, those found in humans, can differentiate to any cell type from one blank canvas. In 2014 a study provided evidence for pluripotent stem cells being the source of regeneration, by regenerating the heart of a monkey from human progenitor cells[1].

Shinya Yamanaka won a Nobel prize for his research into stem cells. His key discovery, in 2006, was a way to create pluripotent stem cells from already specialised cells[2]. These ‘induced’ pluripotent stem cells are one of two sources for human stem cells, the other being ES (embryonic stem cells) - found in developing embryos. Going back to the monkey, the fact that it was progenitors from ES cells repairing its heart shows the potential for human regeneration through these cells. Induced pluripotent stem cells may also play a role; being able to reprogramme them for an exact purpose could mean the potential to repair any part of the body.

Photon-2 microscope image of transplanted embryonic stem cell growth
In the lung, embryonic stem cells have been used to regrow huge amounts of tissue. The two pictures show lung tissue at 6 weeks after stem cells have been transplanted, and again after 16. The darker background are the host lung cells, whilst the green structures have all originated from stem cells! Image credit: Weizmann Institute of Science

Heterochromatin


The division of existing cardiomyocytes must also be considered by researchers. The reason our heart cells don’t return to a state where they can proliferate is because they are blocked. Studies have shown that a protein, heterochromatin, accumulates in cells as the cardiomyocytes mature[3]. The protein prevents the cardiomyocytes returning to a primitive, proliferating state.

Researchers are working on a way to temporarily ‘knock down’ heterochromatin, allowing adult myocytes to re-enter their cell cycles and revert to a state where they can regrow through cell division. RNA could be used to disrupt the protein, and labs are looking at using nanoparticles to deliver it[3]. Furthermore, when a heart attack occurs and cardiomyocytes die from the lack of oxygen, scar tissue is left behind. This tissue is simple to find, so the protein manipulation system could be easily localised to the scarring through injection, making it a very accurate method for damage repair. The disruption of heterochromatin would have to be reversible, so that the effects would wear off once healing is complete and the cells could produce strong contractions again after re-maturation.

Neuregulin

Another way of encouraging regeneration through cardiomyocyte division could be to introduce the hormone neuregulin. Hormones are signalling molecules, transported through the body and used to control a wide range of physiological functions, including eating, sleeping and breathing. They work by binding to specific ‘receptors’ on cells which then elicits a response from them. For example, if a pathogen is detected in our bloodstream, hormones are released to trigger cell reactions in the immune system to fight the virus. Studies have found that neuregulin binds with receptor ERBB2 to promote cardiomyocyte proliferation,[4], but levels of the hormone usually decrease about a week after birth. Research using mice has now shown that by using neuregulin to stimulate the ERBB2 signalling system after a heart attack, the lost and damaged cardiomyocytes can be replaced. Though the experimental evidence is only with mice at the moment, this may offer another promising cell division option for heart regeneration in humans.

Auxin

Cardiomyocytes could also be created synthetically, through engineered stem cells. Yeast cells have been programmed to ‘talk’ to each other via a plant hormone; auxin. Eventually synthetic stem cells could be engineered to communicate too, which is essential when cells have to ‘work together’ to build complex tissues or organs. Communication on this level is essentially a signal from one cell producing a response in another. A team managed to induce auxin synthesis in a ‘sender’ yeast molecule, which was then released[5]. A ‘receiver’ cell was affected and the communication was visible because the yeast cells, which were made to glow fluorescent green, changed to red when the auxin was ‘received’. One major significance of auxin being a plant hormone is that it is generally ignored by mammalian cells. Consequently, this technology could potentially be used in humans without triggering any unwanted or adverse reactions within the body.

The UK Heart Research Institute estimates that in this country alone, every hour ten people die of a heart attack[6]. Furthermore, there are around one and a half million people living in the UK that have survived a heart attack and are living with the dire health consequences. Could we create a treatment for repairing these victims’ hearts? Could we improve hearts that are being damaged by other conditions? Could our understanding of regeneration one day incorporate other parts of our bodies, like regrowing limbs for paraplegics? Though these are questions are tantalisingly close to having conclusions, for now they remain unanswered.

This article was written by Joshua Fleming, a biological sciences student from the University of Leicester conducting a summer internship as a science writer at TWDK.

References
why don't all references have links?

[1] Chong, James J. H., Xiulan Yang, Creighton W. Don, Elina Minami, Yen-Wen Liu, Jill J. Weyers, and William M. Mahoney et al. 2014. 'Human Embryonic-Stem-Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts'. Nature 510 (7504): 273-277. doi:10.1038/nature13233.
[2] Takahashi, Kazutoshi, and Shinya Yamanaka. 2006. 'Induction Of Pluripotent Stem Cells From Mouse Embryonic And Adult Fibroblast Cultures By Defined Factors'. Cell 126 (4): 663-676. doi:10.1016/j.cell.2006.07.024.
[3] Sdek, P., P. Zhao, Y. Wang, C.-j. Huang, C. Y. Ko, P. C. Butler, J. N. Weiss, and W. R. MacLellan. 2011. 'Rb And P130 Control Cell Cycle Gene Silencing To Maintain The Postmitotic Phenotype In Cardiac Myocytes'. The Journal Of Cell Biology 194 (3): 407-423. doi:10.1083/jcb.201012049.
[4] D’Uva, Gabriele, Alla Aharonov, Mattia Lauriola, David Kain, Yfat Yahalom-Ronen, Silvia Carvalho, and Karen Weisinger et al. 2015. 'ERBB2 Triggers Mammalian Heart Regeneration By Promoting Cardiomyocyte Dedifferentiation And Proliferation'. Nat Cell Biol 17 (5): 627-638. doi:10.1038/ncb3149.
[5] Khakhar, Arjun, Nicholas J. Bolten, Jennifer Nemhauser, and Eric Klavins. 2015. 'Cell–Cell Communication In Yeast Using Auxin Biosynthesis And Auxin Responsive CRISPR Transcription Factors'. ACS Synth. Biol., 150706075349008. doi:10.1021/acssynbio.5b00064.
[6] Heart facts, Heart Research Institute, 2015. (web).