Young-Jae Nam, M.D., Ph.D.

Profile

A fundamental, but unsolved problem in heart diseases is irreversible loss of cardiomyocytes that is replaced by fibrotic scar in response to injury. Therefore, to convert cardiac fibroblasts, the most abundant cell type in the heart, into cardiomyocytes after injury is a particularly attractive heart repair strategy. Over the last four years, we have taken three fundamental steps toward this goal: 1) in vitro reprogramming of adult mouse fibroblasts into beating cardiomyocytes by forced expression of four transcription factors, 2) developing in vivo reprogramming strategy targeting activated cardiac fibroblasts after myocardial infarction, which improved heart function and reduced scar formation, and 3) identifying the optimal combination of factors that is necessary and sufficient to induce a contractile phenotype in adult human fibroblasts.

There are three major types of cardiomyocytes in the heart as defined by anatomical location and unique electrical properties: atrial, ventricular, and pacemaker. Highly coordinated activity of all three cardiac subtypes is required for effective blood pumping. Thus, significant loss or dysfunction of individual cardiac subtypes can lead to specific forms of potentially life-threatening heart disease depending upon the identity of the affected cell type. However, all current heart repair strategies have been focused on regeneration of heart muscle without subtype specification. The inability to specify subtype of cardiomyocytes has been a main barrier to clinical application of newly generated muscle cells derived from either differentiation or reprogramming method. Therefore, an ideal heart repair strategy would be able to selectively generate the right type of heart cells in the right place of the heart depending on the type of heart disease. Thus, our research goals are 1) to develop an entirely new heart repair strategy targeting specific heart disease by generation of individual subtypes of cardiomyocytes including atrial, ventricular, and pacemaker cardiomyocytes and 2) to understand the mechanistic basis of cardiac cell fate specification during direct cardiac reprogramming and pluripotent stem cell differentiation.

Toward this goal, our research focus is to generate individual subtypes of cardiomyocytes including atrial, ventricular, and pacemaker cardiomyocytes by direct reprogramming of fibroblasts and forward programming of iPSCs (induced pluripotent stem cells) to subtypes of cardiomyocytes. After these initial goals are achieved, clinical potentials of this new strategy will be examined in human cells and in vivo heart disease mouse models.

Publications

The following timeline graph is generated from all co-authored publications.

1. Generation of Nppa-tagBFP reporter knock-in mouse line for studying cardiac chamber specification. Zhang Z, Zhang Q, Lal H, Nam YJ (2019) Genesis 57(6): e23294
   › Primary publication · 30920727 (PubMed)
2. Generation of MLC-2v-tdTomato knock-in reporter mouse line. Zhang Z, Nam YJ (2018) Genesis 56(10): e23256
   › Primary publication · 30307112 (PubMed) · PMC6294655 (PubMed Central)
3. High content analysis identifies unique morphological features of reprogrammed cardiomyocytes. Sutcliffe MD, Tan PM, Fernandez-Perez A, Nam YJ, Munshi NV, Saucerman JJ (2018) Sci Rep 8(1): 1258
   › Primary publication · 29352247 (PubMed) · PMC5775342 (PubMed Central)
4. The Promise of Cardiac Regeneration by In Situ Lineage Conversion. Nam YJ, Munshi NV (2017) Circulation 135(10): 914-916
   › Primary publication · 28264888 (PubMed) · PMC5410767 (PubMed Central)
5. Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Nam YJ, Lubczyk C, Bhakta M, Zang T, Fernandez-Perez A, McAnally J, Bassel-Duby R, Olson EN, Munshi NV (2014) Development 141(22): 4267-78
   › Primary publication · 25344074 (PubMed) · PMC4302916 (PubMed Central)
6. Heart repair by cardiac reprogramming. Nam YJ, Song K, Olson EN (2013) Nat Med 19(4): 413-5
   › Primary publication · 23558630 (PubMed) · PMC3790637 (PubMed Central)
7. Reprogramming of human fibroblasts toward a cardiac fate. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K, Hill JA, DiMaio JM, Baker LA, Bassel-Duby R, Olson EN (2013) Proc Natl Acad Sci U S A 110(14): 5588-93
   › Primary publication · 23487791 (PubMed) · PMC3619357 (PubMed Central)
8. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN (2012) Nature 485(7400): 599-604
   › Primary publication · 22660318 (PubMed) · PMC3367390 (PubMed Central)
9. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, Dorn GW, van Rooij E, Olson EN (2011) Circ Res 109(6): 670-9
   › Primary publication · 21778430 (PubMed) · PMC3167208 (PubMed Central)

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