The Epstein Laboratory studies cardiovascular development, the genetics of congenital heart disease and cardiovascular regenerative and stem cell biology. The lab has a long-standing interest in congenital heart defects involving the outflow tract of the heart, the role of neural crest, the epicardium and the second heart field. More recent areas of focus include the cardiac inflow tract and the pulmonary veins and the origin of anomalous pulmonary venous return.
Other areas of interest include the factors and genes involved in progressive lineage restriction of cardiac progenitor cells and the role of epigenetics in progenitor cell expansion and differentiation. The lab is also interested in the implications of these studies for the development of new therapies for adult cardiovascular disorders including heart failure and arrhythmia. Specific projects have focused on the role of Notch and Wnt in cardiac progenitors, semaphorin signaling in the developing vasculature, the function of a novel homeobox gene Hopx and histone deacetylases in stem cells and the heart, and the role of the type I Neurofibromatosis gene (Nf1) in mouse and zebrafish cardiac development.
The Epstein Laboratory studies molecular mechanisms of neural crest and cardiac development, with a particular interest in applying lessons learned from developmental models to the understanding and therapy of adult diseases. Neural crest can differentiate into a multitude of cell types including nerve, bone, vascular smooth muscle and melanocytes. Defects in neural crest can lead to common forms of congenital heart disease. We have used mouse models to elucidate a molecular cascade involved in cardiac neural crest migration and differentiation, implicating members of the BMP, Notch, Semaphorin, myocardin, Pax and T-box families in this process. This work has direct relevance to the understanding of the genetic basis of congenital heart disease.
We have also used neural crest as a model of stem cell biology, and we have identified adult neural crest stem cells that reside in the hair follicle and give rise to regenerating melanocytes. Here, Pax3 plays a critical role both in determining cell-fate specification, and also in maintaining the undifferentiated stem cell phenotype until external signals, including induced by Wnt signals, trigger changes in transcriptional complexes and melanocyte differentiation.
Our studies have implicated important interactions between neural crest and other cell types, including vascular endothelium. We have discovered a novel member of the Plexin/Semaphorin family, PlexinD1, expressed by endothelial cells that is required for normal cardiovascular patterning. We have also demonstrated a critical endothelial function for the product of the type 1 Neurofibromatosis gene (NF1), which is a tumor suppressor gene mutated in von Recklinghausen Neurofibromatosis, a disease characterized by neural crest tumors and cardiovascular defects. This work has led to the appreciation for Ras signaling in epithelial-mesenchymal transformation in the heart and suggests that a common mechanism of cardiovascular defects in a series of childhood disorders, including Noonan's syndrome and NF1. We are also using zebrafish models to exploit the ease of evaluation of the developing vasculature in our NF1 and Plexin studies.
Application of the elucidation of embryonic programs to adult disease is best exemplified by our work with a novel homeodomain factor called Hopx. Hopx is expressed early in cardiac development, but also functions in adult cardiac hypertrophy, and it is significantly down-regulated in human heart failure. Hopx functions in association with HDAC2, a member of the histone deacetylase chromatin remodeling family. We have shown that HDAC inhibitors are potent anti-hypertrophic agents, and our ongoing work suggests that HDAC2 is a critical molecular target of HDAC inhibitors in the heart. Our work suggests that Hopx and HDAC2 regulate the fetal gene program during development, and again in the setting of adult disease when the fetal program is reactivated. Evaluation of these adult mouse models of heart disease is facilitated by imaging, microsurgery and invasive hemodynamic and electrophysiologic techniques that we have developed or refined to mimic all of the diagnostic tools available to the human adult cardiologist allowing us to develop new therapeutic targets for congestive heart failure.
Most recently, we have discovered that Hopx is also expressed in many adult stem cell populations and may function as part of a regulatory circuit for maintaining stemness in adult tissues.
Pseudo-colorized images of the forming vascular plexus and epicardium growing over the developing heart are shown. This process contributes to the development of the coronary arteries.
The image shows a corrosion cast of the vasculature of a mouse with congenital heart disease similar to that seen in DiGeorge syndrome.
Other Research Projects
- Expansion of cardiac progenitors by Wnt and Notch
- Histone deacetylase function in cardiac development and the adult heart
- Neurofibromin in cardiovascular development
- Semaphorin signaling and development of the pulmonary veins
- Development of the cardiac conduction system
- Pax3 and neural crest development
The Epstein Lab is comprised of post-doctoral research investigators, research specialists, physicians, fellows and graduate students.
- Aghajanian, Haig
- Engleka, Kurt
- Gupta, Mudit
- Jain, Raj
- Li, Deqiang
- Li, Jun
- Liu, Feiyan
- Manderfield, Lauren
- Wang, Qiaohong
The Epstein Lab of the Penn Cardiovascular Institute publishes the findings of its clinical research in the nation's leading clinical journals.
- Aghajanian, H., Choi, C., Ho, V.C., Gupta, M., Singh, M.K., Epstein, J.A.Semaphorin 3d and Semaphorin 3e Direct Endothelial Motility through Distinct Molecular Signaling Pathways. J Biol Chem. 2014 Jun 27;289(26):17971-17979.
- Wolman, M.A., de Groh, E.D., McBride, S.M., Jongens, T.A., Granato, M., Epstein, J.A. Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficitsin a Zebrafish Model of Neurofibromatosis Type 1. Cell Reports. 2014 September 8, 1–6.
- Degenhardt, K., Singh, M.K., Aghajanian, H., Massera, D., Wang, Q., Li, J., Li, L., Choi, C., Yzaguirre, A.D., Francey, L.J., Gallant, E., Krantz, I.D., Gruber, P.J., Epstein, J.A. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature Medicine, 2013 Jun;19(6):760-5. PMC3746328.
- Takeda, N., Jain, R., Li, D., Li, L., Lu, M.M., and Epstein, J.A. Lgr5 Identifies Progenitor Cells Capable of Taste Bud Regeneration after Injury. PLoS ONE 2013 Jun 8;8(6):e66314. PMCID:PMC3688887.
- Zhao, T., Gan, Q., Stokes, A., Lassiter, R., Wang, Y., Chan, J., Han, J., Pleasure, D., Epstein, J. and Zhou, C. Beta-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation. Development 2014 Jan;141(1):148-57. PMCID:PMC3865756.
- Degenhardt, K., Singh, M.K., Epstein, J.A. New approaches under development: cardiovascular embryology applied to heart disease. J Clin Invest. 2013 Jan 2;123(1):71-4. PMCID:PMC3533277.
- Meadows, S.M., Ratliff, L.A., Singh, M.K., Epstein, J.A., Cleaver, O. Resolution of defective dorsal aortae patterning in Sema3E deficient mice occurs via angiogenic remodeling. Dev Dyn. 2013 May;242(5):570-80.
- Takeda, N., Jain, R., LeBoeuf, M.R., Padmanabhan, A., Wang, Q., Li, L, Lu, M.M., Millar, S., and Epstein, J.A. Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells. Development, 2013 Apr;140(8):1655-64. PMCID:PMC3621484.
- Singh, N., Gupta, M., Trivedi, C.M., Singh, M.K., Li, L., Epstein, J.A. Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression. Dev Biol. 2013 May 15;377(2):333-44. PMCID: PMC3652235.
- Rentschler S, Yen AH, Lu J, Petrenko NB, Lu MM, Manderfield LJ, Patel VV, Fishman GI, Epstein JA. Myocardial notch signaling reprograms cardiomyocytes to a conduction-like phenotype.. Circulation. 2012;126:1058-66. PMID: 22837163
- Manderfield LJ, High FA, Engleka KA, Liu F, Li L, Rentschler S, Epstein JA. Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation. 2012;125:314-323. PMCID: 3260393.
- Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, Tabin CJ. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev Cell. 2012;22:639-650. PMCID: 3306604.
- de la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev Cell. 2012;22:244-254. PMCID: 3285259.