Regulators of Cardiomyocyte Proliferation

Cardiac muscle cells, or cardiomyocytes, are difficult to target in regenerative techniques as they exit the cell cycle early on in development2. In humans, cardiomyocytes have the unique ability to duplicate their nucleus as if they are going to under cellular division, but never actually split into two distinct cells9. These cells are called “binucleated,” and no longer undergo regular cell growth, referred to as proliferation. While mononucleated cells can still divide, the inability of a majority of the heart to regenerate makes therapeutic options following any injury incredibly difficult. Heart regeneration also does not increase following myocardial infarction (heart attack), making it a damaging and therapeutically difficult process2. The limited availability of therapeutic options has contributed to the immense burden of heart disease in terms of both mortality and economic costs.

Figure 1. Flow chart illustrating the role of binucleation in limiting cardiomyocyte proliferation. Figure created in BioRender.com

During early development, cardiac cells are mononucleated and undergo rapid cell growth in order to develop a fully functional heart9. There is an emerging field of thought that aims to understand the signaling pathways that regulate cell growth during this time frame. Signaling pathways are a form of cellular communication where an external molecule, called a ligand, binds to a transmembrane receptor and elicits secondary responses within the cell. These cascades often lead to changes in gene expression, which can promote cell division (mitosis). The idea is that manipulating these pathways by overexpressing different proteins involved in cardiac proliferation could allow binucleated cells to re-enter the cell cycle. It is also possible to utilize these proteins to allow stem cells to differentiate into cardiac cells (see our page about cardiac stem cells). Overall, a well-rounded knowledge of key signaling events, and understanding what pathways actually makes a cardiac cell a cardiac cell is very important in developing regenerative therapies. These downstream effects include the synthesis of many key proteins, including myosin (for heart contraction) and troponin (for more details, refer to our page detailing the mechanisms of the heart).

While there is an incredibly complex network of signaling pathways that all work in tandem to regulate cardiomyocyte proliferation, the following are well studied pathways that have the potential to be applied to therapeutics (Figure 1). In general, this knowledge can assist scientists in manipulating stem cells and other pre-existing cardiac cells to differentiate and proliferate as cardiomyocytes do during embryonic development.

Figure 2. Overview of some of the many signaling pathways involved in cardiac development. All pathways mentioned on this page are bolded. Figure adapted from Cahill et al., 20172 and made in BioRender.com

1. Hypoxia-inducible factor 1α

While it is well known that cardiomyocytes stop proliferating following early stages of development, the mechanism by which this happens is poorly understood. One potential hypothesis has to do with environmental cues following birth. The uterus can be defined as a hypoxic environment, meaning there is not a lot of available oxygen. During this time, the cells rely primarily on glycolysis and anaerobic respiration as an energy source, as oxygen is required to drive oxidative phosphorylation9. However, upon birth, the body is exposed to “normoxia,” which is a term used to describe conditions of “normal” oxygen relative to the Earth’s atmosphere. This transition from hypoxia (no oxygen) to normoxia (normal oxygen) is often accompanied by the cell cycle arrest described above. For more on the metabolism of the heart, refer to our page on cardiac mechanisms.

Figure 2. Flow chart depicting the different oxygen concentrations before and after birth and the resulting effect on proliferation via binucleation. Figure created in BioRender.com

It is hypothesized that this transition into an oxygen-rich environment (promoting aerobic respiration) encourages the deactivation of transcription factors that are only expressed in hypoxic environments, such as hypoxia-inducible factor 1α (HIF1α). Established regenerative therapies that induce cell cycle re-entry do result in increased expression HIF1α9. In addition, hyperoxia in the uterine environment, meaning higher than average oxygen concentration, causes cardiac cells to stop dividing earlier than expected9. As such, it is possible that the oxidative phosphorylation promoted by normoxia encourages binucleation through the downregulation of important transcription factors, such as HIF1α (Figure 2).

2. FGF1, Neuregulin 1, and p38

Mitogen-activated protein kinases (MAPK) are a highly conserved family of enzymes involved in many different pathways promoting cellular proliferation by a phosphorylation cascade (more on the mechanism of kinases on mechanisms of the heart)10. In cardiac differentiation, or the process by which cells begin to express genes that are specific to the heart’s function, signaling pathways involving MAPK p38 inhibit a variety of transcription factors that allow for proliferation to proceed. As such, MAPK p38 is involved in cell cycle arrest following the developmental period. Inhibition of MAPK p38, in opposition, promotes proliferation and regeneration.

The MAPK p38 pathway is also linked with fibroblast growth factor 1 (FGF1) and neuregulin-1 (NRG1) signaling pathways (see Figure 3). The FGF1 ligand binds to a receptor on the cells surface, often denoted as FGFR, which then promotes a series of downstream signaling pathways, including the activation of phosphatidylinositol-3-kinase (PI3K) (Figure 3). PI3K is an intracellular kinase that plays an important role in cell growth and survival10. The NRG1 protein ligand similarly binds to its extracellular receptor, indirectly activating PI3K (Figure 3). PI3K is also downregulated by p38, a kinase known to cause cell cycle arrest. While the exact mechanism by which these molecules promote cell cycle re-entry isn’t well known, the fact that these pathways share PI3K as common signaling factor indicates the protein likely regulates downstream events that are key to cardiac proliferation. Inducing overexpression of FGF1 and NRG1 in animal models has been shown to promote cardiac cell regeneration, making it a potential therapeutic model10.

Figure 3. Overview of the FGF1, NRG1 and p38 signaling pathway regulating cardiomyocyte differentiation. Figure adapted from Xin et al., 201310 and created in BioRender.com

3. Hippo/YAP signaling pathway

The Hippo/Yes-associated protein (YAP) pathway is another evolutionarily conserved signaling casvade involved in cellular proliferation and viability during the early stages of development10. The YAP1 protein is a transcription factor that when phosphorylated, can no longer enter the nucleus to promote gene expression. YAP1 is phosphorylated following multiple upstream signaling events initiated through the Hippo pathway (Figure 4). The phosphorylated protein is no longer active, which then impedes cardiomyocyte proliferation. Downregulation or deletion of upstream signaling molecules in this cascade, such as SAV and LATS2 (see Figure 4), have been shown to promote proliferation in cells10.

By contrast, activated non-phosphorylated YAP contributes to proliferation by promoting the insulin-growth factor (IGF1) signaling pathway10. This pathway also involves PI3K, which is upregulated in the process, as was the common feature in FGF1 and NRG1 signaling (Figure 4). The IGF pathway promotes cardiac proliferation by phosphorylating a complex of proteins known to deactivate beta-catenin. YAP and beta-catenin form a transcription factor complex that can then upregulate a variety of genes associated with cardiomyocyte proliferation and viability.

To summarize, these three signaling pathways operate by either activating or deactivating beta-catenin and YAP, with the phoshorylated forms of each protein being inactive. Both proteins are essential in the transcription of cardiac-related genes and cell cycle entry during early development10. The Hippo pathway downregulates this transcription factor complex, while IGF1 and WNT work to dephosphorylate beta-catenin, thereby promoting cell cycle entry. The WNT pathway, in addition to Hippo/YAP and IGF signaling, are therefore commonly targeted in stem cell differentiation10 (for a specific example of WNT up regulation, look at our page on stem cell differentiation).

Figure 4. Overview of the Hippo/YAP, WNT, and IGF pathways involved in cardiomyocyte viability and proliferation. Figure adapted from Xin et al., 201310 and created in BioRender.com

Conclusion

Cardiomyocyte regenerative therapies are complicated by the fact that a majority of cardiac cells stop dividing following a period of early development. Understanding what pathways are more active during developmental periods, in addition to what pathways are known to encourage cells that have exited the cell cycle to continue dividing, is incredibly important in the application of regeneration. Developmental knowledge is applied in stem cell therapeutics, which often utilize overexpression of the above pathways to promote differentiation to cardiac cells. Above, we have summarized just a few of the signaling pathways of interest, but there is still so much more to be known.

68 Comments

  1. I really like how this page moves from defining the problem (cell cycle arrest), to the factors involved, and then the specific pathways! Additionally, the infographics are very thorough and well-done, it’s a super helpful resource to have, especially with pathways. A couple of points I wanted to make; firstly, you say “the following are well studied pathways that have the potential to be applied to therapeutics”, and while you address why this might be the case in the conclusion, I think it would make it more clear if you explicitly defined why you thought these pathways in particular have a case for therapeutics before you start talking about them. Secondly, I mentioned this in a previous comment but a working link + citation number in the figure caption would be very helpful for readers to look more into the pathways you’ve described. Lastly, to keep the format more consistent, I would look into breaking up this page into subpages (like the last page). I thought that made the pages easier to read. Overall, super well done!

  2. Joaquin T. de Jesus

    December 8, 2023 at 2:55 pm

    I was watching a health documentary and they mentioned people with poor circulation, due to size or arterial clogging, end up developing a bigger heart to pump blood more effectively. I was wondering how the heart can grow in size even if the cells, specifically these cardiomyocytes, are not able to replicate. Might be the case that it bigger heart becomes strained because of the lack of proliferation, which, when pumping bigger volumes of blood, causes damage? Curious to know what y’all think. I also just thought it was really interesting to see a signalling pathway, which we recently covered in class, in your project. It’s interesting to see the many proteins involved in regulating cell proliferation. The specificity and nuance of the expression of those developmental proteins is shown quite clearly here.

  3. Katerina V. Varsamis

    December 8, 2023 at 3:37 pm

    I did not know about binucleated cardiomyocytes and their effects on heart regeneration, that was extremely interesting to read about! I personally really enjoyed the use of figure 1 as a summary of all the important pathways. It was much more meaningful explanation to me than a sentence would have been. I overall felt as though you offered a very good introduction to the complexities involved in regulating cardiomyocyte proliferation, as well as a detailed overview of the key signaling pathways. If you decide to add more to this section, I was interested in learning more about the specific molecular mechanisms by which these pathways interact and regulate cardiomyocyte proliferation. Here are some specific questions I encountered while reading: are there known downstream effectors or key genes influenced by these pathways that directly impact the cell cycle re-entry of cardiomyocytes? In general, further exploring these molecular details could act as a jumping-off point to delve into even more depth on these topics.

  4. The explanation of binucleation is very effective for contextualizing the severity of cardiac damage!

    I also think the choice to bold mentioned terms for figure 2 was very helpful for general readibility.

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