Cardiomyocyte Differentiation from Stem Cells and Fibroblasts
Stem cells are the body’s master cells, used to generate all specialized cells within the human body11. In 2006, two scientists Takahashi and Yamanaka published a detailed procedure outlining the reprogramming of mouse embryonic cells and fibroblasts back into stem cells, called induced pluripotent stem cells since they were created non naturally, by introducing and regulating various growth factors12. The procedure outlined in this paper was quickly translated to humans, and from human somatic cells, such as skin and blood cells, human-induced pluripotent stem cells or hiPSCs were created.
HiPSCs have a multitude of uses within cardiac therapeutics. As the heart matures, cardiac cells called cardiomyocytes enter a terminal stage where they no longer divide and produce new cells13. This makes recovery from events or diseases that are harmful to the cardiac tissue very difficult, as most damage tends to be almost permanent. More information on this can be found here. To remedy this, many therapeutic companies are researching the use of hiSPCs in creation of cardiomyocytes, which can be applied to the damaged myocardium in the form of a hydrogel or a cardiac patch. These newly generated cardiomyocytes then integrate with the existing cells to create a heart with increased function.
Creation of Cardiomyocytes From Human Induced Pluripotent Stem Cells
The first step in creation of many regenerative cardiac therapeutics is the generation of cardiomyocytes from hiPSCs. To do this, there are three main signaling pathways within the stem cell that are commonly manipulated: the BMP4 pathway (Figure 1), the Wnt pathway (Figure 2), and the FGF pathway (Figure 3)14. While these are three commonly manipulated pathways, this is not an exhaustive list and other methods of cardiomyocyte creation from hiPSC have been used.
Bone Morphogenetic Protien (BMP4) Signaling Pathway
The first pathway that must be manipulated is is the BMP4 signaling pathway. Bone Morphogenetic Protein or BMP4 is a growth enzyme, which must be upregulated to initiate creation of the cardiomyocyte as explained below. The pathway is shown below in Figure 115.
In this pathway, BMP binds to BMP 1 & 2 receptors which activates Receptor Regulated Suppressor of Mothers against Decapentaplegics (RSMADs) 1, 5 & 8. SMADs are proteins which act to transmit a signal given by a growth enzyme to the nucleus in order to regulate gene expression16. In this pathway, SMADs 1,5 and 8 together with Coactivator SMAD 4 form a complex which enters the nucleus and activates target gene expression15.
The expressed gene via upregulation of the BMP4 pathway helps to guarantee the cells to be mesodermal17 . The mesoderm is the middle layer of an embryo, and mesodermal cells proceed to form blood, muscle, bone or connective tissue cells17. Cardiomyocytes belong to this category of cell.
Wingless/integrated (Wnt) Signaling Pathway
The second pathway that must be regulated within a hiPSC is the Wingless/integrated or Wnt pathway. Wnts are proteins that help to regulate many cell functions including cell fate, which is what kind of cells stem cells are differentiated into18. This is important in the determination of the hiPSCs to cardiomyocytes. The Wnt singaling pathway is shown below in Figure 219.
There are two pathways within the Wnt signaling pathway. One is dependent on β catenin, called a canonical pathway, and one is independent of β catenin, a non-canonical pathway.
Canonical Wnt Pathway
Firstly, Wnt binds to both the Frizzled and the low density lipoprotein receptor-related protein or LRP. In the canonical pathway, the binding of the protein to these receptors activates the Dishevelled protein family which in turn inhibits a multiprotein complex. By inhibiting this complex, β catenin production is upregulated. β catenin is the protein responsible for transmitting the signal from the Wnt proteins to the nucleus20. This triggers transciption of genes that are crucial in establishing the fate of the cell from a mesodermal fate to cardiac mesodermal fate18.
Non-Canonical Pathway
The β catenin independent pathway results in the upregulation of two proteins Rac and Rho from DSH which in turn activate c-Jun N-terminal kinase (JNK) and Rho-associated kinase (ROCK). This activates Activating transcription factors /cAMP response element binding protein (ATF/CREB) which in turn activates target gene expression. In addition, the binding of Wnt to receptors upregulates Ca2+ which activates Ca2+/calmodulin-dependent kinase 2 (CamK2) and the protein kinase (PK)C. This pathway regulates calcium ion concentration within the cell21.
Current research is unaware of the exact effects of upregulation and down regulation of this pathway21. However, research has shown positive effects when upregulated early in the cellular culture process, but downregulated as the process proceeds, which can be acomplished with a Wnt inhibing enzyme called DKK1, which competitively binds to the LRP5/6 receptor of Wnt21.
Fibroblast Growth Factor (FGF) Pathway
The third and final pathway that must be regulated in the creation of cardiomyocytes from stem cells is the FGF signaling pathway, which is also a growth factor22. This pathway also assists in the generation of mesodermal cells from hiSPCs, as well as the differentiation of these cells into cardiac cells23. This pathway is shown below in Figure 3.
In this pathway, FGF binds to the FGF receptor which activates fibroblast growth factor receptor substrate 2 (FRS2α) which is a docking protein. This is followed by activation a complex of two proteins which in turn activate g protien RAS . This activates a cascade of proteins including rapidly accelerated fibrosarcoma (or RAF) kinase, the Mitogen-activated protein kinase (MEK) kinase, and the mitogen-activated protein kinase (MAPK). Finally, MAPK phosphorylates target transcription factors in the nucleus which activates gene expression15.
Once the BMP4, Wnt, and FGF signaling pathways are properly regulated, cardiomyocytes can be created from hiSPCs. Other methods for cardiomyocyte creation from stem cells add additional growth factors, but these three are commonly used in all laboratories14. When the challenge of differentiating cardiomyocytes from stem cells is combatted, the newly created cells can be used in regenerative medicine therapies for cardiac repair such as the cardiac patch or hydrogels.
Regulators Involved in Reprogramming Fibroblasts to Cardiomyocytes
A new field of cardiac regenerative medicine revolves around reprogramming cells that already exist in the environment into cardiac cells in vivo. This would eliminate some of the immunogenic factors of injecting foreign stem cells by manipulating the patient’s own pre-existing cardiac system. Scientists have looked at ways to promote the transition of cardiac fibroblasts either directly to cardiomyocytes or through a pathway that first induces the development of pluripotent stem cells (iPS). Previous research has illustrated that differentiation of fibroblasts can be accomplished through the direct approach by adding only 3 transcription factors: GATA4, MEF2C, and TBX5, collectively called GMT factors (Figure 3)10.
All of these transcription factors are involved in many signaling pathways at early stages in cardiac development, including the Wnt pathway24. They are also unique in that they can recruit other transcription factors to form large complexes necessary for cardiac gene expression25. Finally, GATA4 is also special in that it can acetylate and deacetlyate multiple other genes. Acetylation of histones affects binding of DNA, making the regions more or less available for expression (a phenomenon called epigenetics). The GMT factors therefore promote the expression of cell signaling pathways essential to a cardiac fate by direct expression, recruitment of other factors, and histone modification.
December 8, 2023 at 1:25 pm
Nice dive into the signaling pathways! There’s a lot of moving pieces and I think you do a good job of breaking it down well, especially with the infographics. I found it very interesting how hiPSCs were created by reprogramming existing cells. A couple of points:
Firstly, I think the first paragraph could use some grammatical updates, just for readability. There is some issues with run on sentences and comma placement.
Second, you talk about “three main signaling pathways” for turning hiPSCs into cardiomyocytes. Are the three pathways you discuss exhaustive? I ask because your language when talking about the pathways themselves seem to suggest that they are conclusively the only 3 pathways to be regulated but the introduction suggests that there are potentially more. I think reconciling this difference would make it easier to understand.
Lastly, the last paragraph in the Wnt pathway is a little confusing. You mention that the pathway is responsible for the upregulation of transcription genes that are required, but then talk about how the upregulation and downregulation of Wnt has unknown effects. I think you are talking about different points but as a reader it obscures my understanding of the effects of the pathway.
Good Work!
December 8, 2023 at 3:07 pm
The discussion of signalling pathways has me thinking about how they’re connected. Specifically, I’m curious what the upregulation of these transcription factors as a therapy would cause in terms of side effects. While I think a novel treatment is interesting in this way, unless the fibroblasts are being reprogrammed externally for a patient, a medication or direct treatment at heart might have a significant array of side effects. This is especially true given the number and complexity of these signalling pathways. But as you mention, the cells would be introduced as a young cardiomyocyte, so that shouldn’t be an issue. Overall, the level of detail on each of the pathways shows you guys really thought about how this therapy might work.
December 8, 2023 at 4:51 pm
I really appreciated the comprehensive explanation of the signaling pathways involved in the creation of cardiomyocytes from hiPSCs. The detailed breakdown of the BMP4, Wnt, and FGF pathways provides a clear understanding of the molecular mechanisms at play during this crucial differentiation process. This detailed exploration not only educated me on the relevant pathways themselves but also helped shed some light on the intricate interplay of molecular factors that orchestrate the transformation of hiPSCs into cardiomyocytes.
I would personally be interested in reading more about the challenges and/or limitations associated with the reprogramming process or the use of hiPSC-derived cardiomyocytes. Addressing potential hurdles, such as variability in differentiation efficiency, could contribute valuable insights into the practical considerations and potential areas for improvement in the application of hiPSCs for cardiac regenerative purposes.
December 8, 2023 at 6:57 pm
Your Britannica definition of mesodermal cells is missing its citation and hyperlink.
December 8, 2023 at 7:02 pm
I love how you tied the molecular pathways to the application and reasoning behind the hydrogels and patches!
It may be helpful to create subsection headers for your pathways like for the Wnt signalling pathway, you could add subheadings for the canonical b-catenin dependent pathway and one for the b-catenin independent pathway.
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