induced pluripotent cells in treating cardiovascular diseases

1. Induced pluripotent stem cells in
cardiovascular diseases

2. Cardiovascular diseases (CVDs)
• An estimate shows that 17.3 million people died from CVDs in
2008, representing 30% of all global deaths.
• The number of people who die from CVDs, mainly from heart
disease and stroke, will increase to reach 23.3. million by 2030
• Group of disorders of the heart and blood vessels
 coronary heart disease -48%
 cerebrovascular disease -25%
 peripheral arterial disease-11%
 rheumatic heart disease – 6%

3. • Treatment Options
 Coronary Angioplasty
 Radiofrequency ablation
 Pacemaker insertion
 Cardiac defibrillator
 Resynchronization therapy
• Risk factors associated with various therapies includes
discomfort and bleeding, blood vessel damages, arrhthymia
Kidney damage.
• hESC therapy could potentially repair and regenerate
damaged heart tissue.

4. Induced pluripotent stem cells
• Overexpression of four genes (or ‘Yamanaka factors’) was able to
turn back the developmental clock of somatic cells .
(Yamanaka et al; Cell,2006)

5. Generating patient-specific iPSCs
• Methods to reprogramme somatic cells
 integrating methods
 non-integrating methods

6. Integrating methods
• Retoviral transduction (eg. Moloney murine leukemia virus)
• Lentiviral transduction (eg.Sendai viruse)

7. Non-integrating methods
• Minicircle vectors
• Protein transduction

8. Cardiovascular disease modelling
• Models for CVDs
 Myocardial infarction(mice)
 arterial thrombosis (rat)
 venous thrombosis (rat)
 venous stasis thrombosis (rabbit)
• Derivation of iPSCs from human somatic cells circumvent the
ethical roadblock associated with the acquisition of hESCs.
• iPSC-CMs can recapitulate the disease phenotype in
humans(Moretti et al,cell,2010) .

9. Modelling the long QT syndrome
• Autosomal dominant inheritance of a 596G/A missense
mutation in the KCNQ1 gene.
• Electrophysiological parameters in iPSC-CMs generated from
two patients with LQTS1 were compared with healthy control.
• Similarly, two other studies reported the use of iPSC-CM
disease models for LQTS2(Itzhaki et al ,Nature 2011.)

10. • The investigators further tested drugs that could either relieve
or aggravate the clinical phenotype of LQTS
• The potential therapeutic effects of nifedipine and pinacidil
was tested in this in vitro model.
• Generation of iPSC-CMs from two patients with Timothy
syndrome (LQTS8)(Yazawa et al, Nature, 2011).
• Timothy syndrome had APs that were significantly prolonged
compared with controls, while atrial and nodal Timothy
syndrome iPSC-CMs did not.

11. significant hurdles still exist in modelling the
more complex cardiovascular diseases using
iPSC technology
• Difficulty in ensuring a purified cardiomyocyte population
from iPSCs .
• The complexities of reproducing a heterogeneous disease
phenotype
• Limitations of modelling essentially adult-onset diseases using
iPSC-CMs.

12. Applications in drug testing and
discovery
• Part of the process of drug development and testing is to
demonstrate that the product does not have any significant
cardiac toxicities.
• To ascertain the cardiac response or side effects of an
individual to a new drug in vitro.
• Targeted gene modification of patient-specific iPSCs

13. Applications in regenerative medicine
Myocardial repair
• Research in regenerative medicine using these cells is still at
an early stage.
Intramyocardial
iPSC-MC delivery
Proper
engrafting
Cytoarchitecture
maintanance
Contractile
perfomance
restoration
Electrical stability
& ventricular wall
thickness
(Nelson et al ,circulation,2009)

14. Conclusion
• Mininizing the potential of transplanted undifferentiated
iPSCs to form teratomas.
• Methods ensuring a purified cardiomyocyte population from
iPSCs.
• Safe and effective methods of cell delivery and ensuring that
transplanted cells remain in the myocardium.

15. References
• Nelson TJ, Martinez-Fernandez A, Yamada S, et al. Repair of
acute myocardial infarction by human stemness factors
induced pluripotent stem cells. Circulation, 2009;120:408e16
• Moretti A, Bellin M, Welling A, et al. Patient-specific induced
pluripotent stem-cell models for long-QT syndrome. N Engl J
Med 2010;363:1397e409
• Yazawa M, Hsueh B, Jia X, et al. Using induced pluripotent
stem cells to investigate cardiac phenotypes in Timothy
syndrome. Nature, 2011;471:230e4