1. Human Embryonic Stem Cell Therapy for Cardiomyocyte Degeneration
Brittney Williams

2. What is a hESC? Human Embryonic Stem Cells Pluripotent cells
capable of differentiating into any cell type
Derived before the embryo would normally implant in the uterus
They originate from the blastocyst

3. How do we get hESC? Derived from in vitro fertilized human embryos
Culture of pluripotent stem cells
Inner cell mass separated from trophectoderm
Inner cell mass cells are plated onto cells to support them
These cells are fed daily and separated every four to seven days
© 2006 Terese Winslow

4. Why are these so controversial?
Moral implication of destroying a human embryo
When does life actually start?
Is a human embryo a child?
Does the destruction of one embryo justify the use as a cure for many people?

5. What are they used for? Tissue regeneration due to injury
Ways to study early development without hurting the resulting child

6. Cardiomyocyte Repair Myocardial infarction (MI) Heart disease
Heart attack
Leading cause of death around the world
Occurs when cardiomyocyte function is loss
Heart disease
Leading cause of death in the Western world
Cardiomyocyte and mitochondrial function decrease

7. hESC-derived cardiomyocyte regulation
Peroxisome Proliferator-activated Receptor-γ Coactivator
(PGC-1)
Repression occurs during cardiomyocyte development
ROS
Control of the ROS levels controls the production of cardiomyocytes
As levels are decreased, PGC-1  is knocked down
Calcium transient amplitude increased
This was discovered through the inhibition of contraction and/or the action potential and calcium transit.
Contraction inhibited by Myosin II ATPase inhibitor blebbistatin
L-type calcium channel inhibitor nifedipine inhibited the AP and calcium transit.

8. What does knowing this mean?
PGC-1 -dependent development stimulates mitochondrial biogenesis
Cardiomyocyte mitochondria are essential to supplying the ATP required during intense heart beating
If this function is damaged, there may be consequences
Most of what we know is derived from a mouse model
These stem cells however are vastly different from humans
The ability to see the model in humans gives more insight to mitochondrial regulation
Cardiomyocyte identity is linked to the mitochondrial biogenesis phenotype

9. Use of hESC-derived cardiomyocytes in rats with MI
To learn the extent of use for these cells, they must be tested in animal trials
Tested in rats with MI to see if myocardial function is improved
Immunosuppressed healthy and infarcted rat hearts were injected with one of four things
Undifferentiated hESCs
hESC-derived cardiomyocytes
Noncardiomyocyte hESC derivatives
Saline
Histological analysis and echocardiography determined the stuctural and functional results

10. What happens when hESCs are implanted?
In Vivo transplant of undifferentiated hESC
Results in teratoma-like structures
No differentiation into the cardiac lineage
In vivo cardiac environment did not enhance hESC cardiomyogenesis
Transplantation of hESC-CMs in a healthy heart
Grafted cells present however no tetratoma structures
Cell grafts consisted of mases of human cells interspersed within myocardium
Transplantation of hESC-CMs in the infracted heart
Grafted cells present with no tetratoma structure
Aligned with host cells with no inflammatory encapsulation
Gap junctions could be identified

11. What happens (cont) Transplant of noncardiomyocyte hESC derivatives
Does not change the remodeling process
No changes detected
Transplant of hESC-CMs improve myocardial performance in the model
Grafting ex vivo pre-differentiated hESC-CMs into infracted hearts showed cardiomyocyte survival and integration into the host cell

12. Citations
Embryonic Stem Cells. (n.d.). Retrieved December 02, 2017, from
Birket, M. J., Casini, S., Kosmidis, G., Elliott, D. A., Gerencser, A. A., Baartscheer, A., … Mummery, C. L. (2013). PGC-1α and Reactive Oxygen Species Regulate Human Embryonic Stem Cell-Derived Cardiomyocyte Function. Stem Cell Reports, 1(6), 560–
Caspi, O., Huber, I., Kehat, I., Habib, M., Arbel, G., Gepstein, A., … Gepstein, L. (2007). Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts. Journal of the American College of Cardiology, 50(19), 1884–