Dr. Joseph Wu

Modeling cardiovascular diseases with stem cells.

Ebert AD, Liang P, Wu JC. 2012. Induced Pluripotent Stem Cells as a Disease Modeling and Drug Screening Platform. J Cardiovasc Pharmacol.

-Burridge PW, Keller G, Gold JD, Wu JC. 2012. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell. 10(1):16-28.

-Plews JR, Gu M, Longaker MT, Wu JC. 2012. Large Animal Induced Pluripotent Stem Cells as Pre-Clinical Models For Studying Human Disease. J Cell Mol Med. 1582-4934.

-Kamileh Narsinh, Kazim H. Narsinh, and Joseph C. Wu. 2011. Derivation of Induced Pluripotent Stem Cells for Human Disease Modeling. Circ Res. 2011 April 29; 108(9): 1146–1156.

Question 1

Dr. Wu can you please tell us a bit about yourself, your career path over the years and how you began studying of cardiovascular diseases with stem cells?

Michael Barresi

Question 2

What effect would the immature hPSC have on modeling cardiac disease? You speculate on the positive and negative consequences of the immaturity on drug testing and regenerative medicine, but what role could they play in modeling disease? Would there be obstacles when trying to model diseases that are not early onset?

Samantha Ross

Question 3

Assuming that sometime in the future cell lines derived from human iPSCs and/or ESCs are approved for human transplantation, and assuming that iPSC- and ESC-CMs and hundreds of other different SC-derived tissue types are available, do you think it might be possible to extend life expectancy far beyond the age it is currently by continuing to replace “old” or “damaged” parts of the body indefinitely?Would you personally approve of this kind of use of SCs?

Sonia Sidhu

Question 4

In the paper Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming, several processes for isolating “pure cardiomyocytes” following attempted differentiation of iPSCs were mentioned. If you’re getting a mix of differentiated cells after graded additions of different factors, does that mean the exact proportions and kinds of factors (and small molecules) to generate certain types of cardiomyocytes haven’t been elucidated yet? Also, Do you have any inkling as to what might be missing from the differentiation process of iPSCs and ESCs to cardiomyocytes such that they are not maturing? Are we missing an entire step with its own “chunk” of factors?

Sonia Sidhu

Question 5

Would the application of de novo cardimyocytes be plausible in infants who were born with a congenital heart disease? For example hypoplastic left heart syndrome where the left side of the heart (mitral valve, left ventricle, aortic valve and aorta) does not develop completely.

Barbara Blank

Question 6

In the review article on “Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming” it is stated that a myocardial infarction, could lead to the needed replacement of 1 billion cells. How would such a large number of cells be produced in a short time?

Barbara Blank

Question 7

For the “Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Programming” article: It states on page 22, in order to reprogram cardiac fibroblasts into cardiomyocyte- like cells “these investigators began with a selection of 14 key genes related to cardiac development…” how were these 14 genes selected out of many different genes? What process did you have to encounter to do so? and why only 14? What defines “key genes”?

Hyunkyung Kang

Question 8

Why do you think certain cell types, such as neural stem cells, can be more easily reprogrammed than others? Does this difference in reprogramming ability in any way affect the viability of certain cells in disease modeling?

Emily Barber

Question 9

You have mentioned many of the pros and cons for using large animals and their iPSCs to model disease, with an overall message that they are more superior then most other forms of research subjects. My question is, if they make such better research models then how come no one else has strongly suggested this before and or has used them more commonly in their research?

Sheila Sernoff

Question 10

What is our current understanding of the epigenetic profiles of stem cells, particularly as it relates to comparing hESC with IPSCs and between IPSC derived from different somatic cells? -Additionally, how limiting is it for a scientist to rely on model animals that don’t cause ethical uneasiness in the public?  Do you feel the reliability and therapeutic applications of IPSCs will reach the point of eliminating the need for hESC?

Alex Jaramillo

Question 11

Because MESP1 is the “master regulator” of cardiac progenitor specification, could you just manipulate the amount of time a hESC or hiPSC is exposed to this gene and see if different cardiac cells arise, and whether or not they respond physiologically?

Gianna Teague

Question 12

According to the review of the methods of iPSC derivation (Narsinh et al.), it seems that RNA delivery is the safest, most faithful, and the most efficient method so far. Has there been any research where cardiomyocytes (or other cardiovascular cells) have been derived from iPSC produced using this method? How widely used is this method?

Haneui Bae

Question 13

Currently in your opinion what are the most pressing unanswered questions in your field of modeling cardiovascular disease with stem cells?

Michael Barresi