Heart Regeneration by Lineages of Stem Cells: The End of All Heart Diseases?

The Heart is an organ with a type of tissue that cannot be repaired itself efficiently to recover its complete function. Hence, we need to find mechanisms that mediate & improve the Cardiac Function after injury.

There are some methods of regeneration, like some which involve the injection of Growth Factors into the arteries that supply the heart itself.
However, we are going to focus on a method that relies on the following:

Cell Therapy by Myocardial Injection

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Cell Therapy is the treatment with living cells to a patient to cure a disease or to cover a lack in something. They can be from anywhere, but the sources of the cells are catalogized into

• Autologous Source (the same person)
• Allogenic Source (a different person)

A type of cell therapy is the Blood Transfusion, as we are introducing (compatible) Red Blood Cells to a person that doesn't have enough due to bleeding for example.
Other fancy Cell Therapies include treatment of diabetes type II, Spinal Cord injuries, Bone Marrow Transplantation or treatment of Heart Injuries.

Our goal is to induce angiogenesis and generate functional myocardium. To do that, it is necessary to:

• Form the muscular tissue
• Form the interconnections between the cells (the so-called intercalated disks) to create a syncytium as seen in the image.

The syncytium is very important as we need to have a heart that contracts rhythmically and organizedly. Otherwise we would have problems with pumping blood to the organism.

To achieve this, Myocardial injection is used, and it is needed to find suitable cells for starting the procedure.
4 lineages have been found to be up for the task.
The following are the descriptions of each and the methods.

1. Endothelial Progenitor Cells (EPCs)

These are a type of cell that are catalogized as a Colony-Forming Unit (CFU), which are a division of cells capable of generating certain lineage of blood cells.

As you could have guessed from their name, these are type of cells which are the mother of all Endothelial cells (cells present in vessels).

They are circulating angiogenic cells, meaning they will create extra blood vessels where necessary, and have been proven to come from Hematopoietic Stem Cells in the bone marrow as they express the same markers in the membrane such as CD133+. However, the process to determine their formation and their circulation is still to be verified.

Data shows that patients with myocardial infarction show an increased level of EPCs, and that increase also comes with more Granulocyte-Colony Stimulating Factors (G-CSF). These G-CSF have the ability to mobilize Stem Cells from the Bone Marrow to the damaged heart and induce the release of some factors for their development.
With EPCs & Bone Marrow stem cells, we can cover the differentiation to cells of cardiac tissue & formation of new vessels for their nourishment.
The mechanism and the idea seem promising. However, G-CSF injections were tested in patients with acute heart infarction, and even though performance was increased, there was zero functional recovery.

2. Satellite Cells (Myoblasts)

These are a type of cells present in skeletal muscle.
They are active and cause regeneration of the tissue in the case of an injury to the muscle. But, we need to reproduce the same effect but in cardiac muscle, not skeletal muscle.
It was found that myoblasts on the heart can fuse with nonmyogenic cells (cells that do not create muscle) in vitro. Later on, experiments on rats confirmed that there was some degree of fusion, although rare.
They don't seem very feasible as they didn't work effectively. But, formation of syncytium was proven to happen.
It confirms that stem cells could theoretically be implanted, differentiated to cardiac cells, and finally fused with healthy cells to replace the damaged ones.

3. Human Embryonic Stem Cells (hESCs)

This type of stem cells are derived from one part of the early embryo, and can be very useful to create cardiac tissue de novo as they have the full potential to become almost any kind of cell in the body.

In the following experiment, mouse Embryonic Stem Cells (mESCs) were used.
First, generation of cardiac cells was induced by producing some structures called Embryonic bodies .
Some of these structures started beating spontaneously after 8 days. Later on, after 20 days, 70% were found beating. Meaning that it is possible to produce heart tissue.

When this experiment was replicated with humans, surprisingly only 1-25% were found beating.
It was suggested that the endoderm (one of the 3 basic layers of the early embryo) played an important role for differentiation.
So one more experiment was done with hESCs but with a cell lineage of endoederm-like: the END-2 lineage.
The result?
The differentiation worked, and the cells starting expressing GATA-4 or MEF-2, which are factors that regulate and make enhanced expression of cardiac cells until their complete differentiation.
However, their formation and implantation in the heart is still challenged, as these cells act as their own pacemakers (beat on their own), which could cause arytmias if implanted. Furthermore, they can be effect of rejection by the body's Inmune System.

4. Mesenchymal Stem Cells (MSCs)

These are a type of cells that are present in embryonic Connective Tissue. They are the highes perecentage of cells within all Bone Marrow Primary Cells (BMPCs).
Their importance derives from their high ability to transdifferentiate easily into cardiomyocytes when injected into mouse myocardium. After induced infarction, even functional improvement was present after transplant!
Again, some factors like the ones mentioned before were present. But also fusion with normal cardiomyocytes!
However, I found conflicted information here, as it was mentioned that these cells transplants were making an improvement because also some EPCs were enhancing with their angiogenesis.

Still, there is a long way to go, and in clinicaltrials.gov, I found this trial which will try these type of cell therapy during Open Heart Surgery, scheduled to finish by 2020. So we will need to wait and see what will be the results.

Conclusion

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Heart recovery after trauma is a reality. Doing it with Cell Therapy has a lot of advantages but achieving it in a functional manner is the difficult part. There are a lot of obstacles to overcome, such as the inmune system rejection, the arytmias it may cause, or even how and where precisely in the heart should the treatment be put into place.
This field for regeneration seems very promising and could lead to a future without any more heart related diseases that are not currently treatable.
However, the whole procedure could be expensive and not accesible to everyone who needs it. So we need to wait what the future will give to us.
Only time will tell.

Closing

This has been a very interesting topic to do a research for. But it has been really difficult as there was conflicting information from different sources, and also it was tough to understand. Anyway, I think it was worth it!
With this post I did something new by putting some easy-to-explain terms as a link to their wikipedia pages so I don't spend time explaining every single small term. However, maybe they were not needed at all? Feedback on it would be really appreciated.
I hoped you have enjoyed the post!
As always,
This is @deholt, signing off!

References

• Gene and Cell Therapy Defined - by the American Society of Gene & Cell Therapy (at asgct.org)
• Hematopoiesis - by Madhumita Jagannathan-Bogdan and Leonard I. Zon at PubMed
• Stem Cell Injection to Treat Heart Damage During Open Heart Surgery – by Pamela G Robey, Ph.D. at clinicaltrials.gov
• Cellular cardiomyoplasty: Myocardial regeneration with satellite cell implantation – by Ray C.-J. Chiu, Audrius Zibaitis, & Race L. Kao at annalsthoracicsurgery.org
• Heart repair and stem cells – by Linda W van Laake, Rutger Hassink, Pieter A Doevendans, & Christine Mummery at PubMed
• Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury – by Theo Kofidis, Darren R. Lebl, Eliana C. Martinez, Grant Hoyt, Masashi Tanaka, & Robert C. Robbins at ahajournals.org
• Effects of G-CSF on left ventricular remodeling and heart failure after acute myocardial infarction – by Takano H., Qin Y, Hasegawa H, Ueda K, Niitsuma Y, Ohtsuka M, Komuro I. At PubMed
• Cardiac regeneration and stem cell therapy – by Joshua M. Hare & Sandra V. Chaparro at PubMed