Under the direction of Dr. Robert J. Schwartz, the Stem Cell Engineering Laboratory is focused on developing a knowledge base and advanced methods for induced pluripotent stem cell therapy to regenerate heart muscle cells (cardiomyocytes). These efforts will help to identify optimal cell types for such therapy and are designed to overcome technical and ethical issues involved in using embryonic stem cells. Methodology currently under development involves direct transdifferentiation of skin cells into cardiomyocytes. Ultimately, in keeping with THI's mission to completely reconstitute a human heart, the vision is to grow these engineered cells on artificial biomatrices.
Within the department, Dr. Jun Wang leads a team working to understand the molecular and cellular basis of heart development and to identify pathways that lead to cardiomyopathy and congenital heart defects.
The Stem Cell Engineering Laboratory is focused on the induction of cardiogenic progenitors using novel molecular techniques with the following objectives:
- To produce more specialized cells (e.g., cardiac pacemaker cells).
- To identify small molecules as catalysts to increase cardiomyocyte production efficiency using specialized drug treatments.
The following achievements represent the current research in the Stem Cell Engineering Laboratory:
- Established a research platform to convert human skin-derived cells into cardiomyocytes.
- Enhanced fundamental understanding of how cardiomyocytes develop the capacity to beat.
- Initiated screening of engineered cells in collaboration with Dr. Edward Yeh's team using novel imaging techniques to track the long-term fate/function of transplanted cells in a mouse heart-attack model.
In the news . . .
July 24, 2012
Researchers Mark Progress in Reprogramming Skin Cells
Into Heart Muscle Cells
Physicians and scientists at THI, working collaboratively with the University of Houston, the Texas A&M Health Science Center in Houston and the Baylor College of Medicine, have shown a new way to convert human skin cells into beating heart cells, according to an article being published in the prestigious Proceedings of the National Academy of Sciences. Dr. Robert J. Schwartz reports.
Dr. Wang's group is focused on understanding how SUMO conjugation affects heart development and function. Recent work from Dr. Wang's lab suggests the importance of balanced SUMO conjugation to heart development; decreased SUMO-1 conjugation in murine hearts caused congenital heart defects, the most common birth defects in the world, and/or cardiomyopathy, the leading cause of death in humans. Ongoing work in Dr. Wang's laboratory seeks to reveal the mechanisms by which SUMO conjugation regulates cardiac development and function.
The following achievements represent the current research in Dr. Wang's laboratory:
- Established critical links between sumoylation (a specialized pathway that regulates protein function) and the development of congenital heart defects and cardiomyopathy.
- Stem cells are unspecialized cells that can multiply through cell division and, being stimulated by appropriate physiologic or experimental conditions, can develop into differentiated cells with tissue- and organ-specific functions.
- Induced pluripotent stem (iPS) cells are stem-like cells artificially derived from already specialized cells by inducing a "forced" expression of specific genes so that they acquire potential to develop into other tissue- and organ-specific cells.
- Transdifferentiation is a process by which a specialized (differentiated) cell transforms into a different type of specialized cell.
- SUMO conjugation, or sumoylation, is a posttranslational modification in which SUMO proteins are covalently and reversibly conjugated to targets, thereby altering the targets' activity.
Director, Robert J. Schwartz, PhD
Current members of Dr. Schwartz's lab:
- Vladimir N. Potaman, PhD, Senior Research Scientist
- Paul Swinton, Assistant Director
- Matthew Robertson, PhD, Research Associate
- Ashley Benham, Postdoctoral Research Fellow
- Allan Prejusa, Research Associate
- I Tsuey-Ming Chen, Research Assistant
- Dariya Tikhomirova, student worker
- Jeehyun Park, Research Assistant
- Jose F. Islas, PhD candidate
- Kou-Chan Weng, PhD candidate
Principal Investigator, Jun Wang, MD, PhD, Senior Research Scientist
Current members of Dr. Wang's lab:
- Li Chen, MD, PhD, Postdoctoral Research Fellow
- Ilimbek Beketaev, MD, Postdoctoral Research Fellow
- Eun Young Kim, PhD candidate
- Ling Qian, Research Assistant
Recent Publications, Robert J. Schwartz, PhD
Islas JF, Liu Y, Weng KC , Zhang SX, Prejusa A, Harger J, Tikhomirova D, Chopra M, Iyer D, Mercola M, Oshima R, Willerson JT, Potaman V, Schwartz RJ. ETS2 and Mesp1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proc Natl Acad Sci USA (submitted)
Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal. 2011;4(196):ra70.
Olaopa M, Zhou HM, Snider P, Wang J, Schwartz RJ, Moon AM, Conway SJ. Pax3 is essential for normal cardiac neural crest morphogenesis but is not required during migration nor outflow tract septation. Dev Biol. 2011;356(2):308-22.
Li D, Hallett MA, Zhu W, Rubart M, Liu Y, Yang Z, Chen H, Haneline LS, Chan RJ, Schwartz RJ, Field LJ, Atkinson SJ, Shou W. Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis. Development. 2011;138(2): 303-15.
Zhang J, Chang JY, Huang Y, Lin X, Luo Y, Schwartz RJ, Martin JF, Wang F. The FGF-BMP signaling axis regulates outflow tract valve primordium formation by promoting cushion neural crest cell differentiation. Circ Res. 2010;107(10):1209-19.
Kang X, Qi Y, Zuo Y, Wang Q, Zou Y, Schwartz RJ, Cheng J, Yeh ET. SUMO-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development. Mol Cell. 2010;38(2):191-201.
Hidaka K, Nitta T, Sugawa R, Shirai M, Schwartz RJ, Amagai T, Nitta S, Takahama Y, Morisaki T. Differentiation of pharyngeal endoderm from mouse embryonic stem cell. Stem Cells Dev. 2010;19(11):1735-43.
Tian Y, Yuan L, Goss AM, Wang T, Yang J, Lepore JJ, Zhou D, Schwartz RJ, Patel V, Cohen ED, Morrisey EE. Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. Dev Cell. 2010;18(2):275-87.
Shirai M, Imanaka-Yoshida K, Schneider MD, Schwartz RJ, Morisaki T. T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation. Proc Natl Acad Sci U S A. 2009;106(44):18604-9.
Niu Z, Iyer D, Conway SJ, Martin JF, Ivey K, Srivastava D, Nordheim A, Schwartz RJ. Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart. Proc Natl Acad Sci U S A. 2008;105(46):17824-9.
Ivey KN, Muth A, Arnold J, King FW, Yeh RF, Fish JE, Hsiao EC, Schwartz RJ, Conklin BR, Bernstein HS, Srivastava D. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell. 2008;2(3):219-29.
Niu Z, Li A, Zhang SX, Schwartz RJ. Serum response factor micromanaging cardiogenesis. Curr Opin Cell Biol. 2007;19(6):618-27.
Liu Y, Asakura M, Inoue H, Nakamura T, Sano M, Niu Z, Chen M, Schwartz RJ, Schneider MD. Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells. Proc Natl Acad Sci U S A. 2007;104(10):3859-64.
Chang DF, Belaguli NS, Chang J, Schwartz RJ. LIM-only protein, CRP2, switched on smooth muscle gene activity in adult cardiac myocytes. Proc Natl Acad Sci U S A. 2007;104(1):157-62.
Iyer D, Chang D, Marx J, Wei L, Olson EN, Parmacek MS, Balasubramanyam A, Schwartz RJ. Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs. Proc Natl Acad Sci U S A. 2006;103(12):4516-21.
Chi X, Chatterjee PK, Wilson W 3rd, Zhang SX, Demayo FJ, Schwartz RJ. Complex cardiac Nkx2-5 gene expression activated by noggin-sensitive enhancers followed by chamber-specific modules. Proc Natl Acad Sci U S A. 2005;102(38):13490-5.
Niu Z, Yu W, Zhang SX, Barron M, Belaguli NS, Schneider MD, Parmacek M, Nordheim A, Schwartz RJ. Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets. J Biol Chem. 2005;280(37):32531-8.
Zhang SX, Garcia-Gras E, Wycuff DR, Marriot SJ, Kadeer N, Yu W, Olson EN, Garry DJ, Parmacek MS, Schwartz RJ. Identification of direct serum-response factor gene targets during Me2SO-induced P19 cardiac cell differentiation. J Biol Chem. 2005;280(19):19115-26.
Barron MR, Belaguli NS, Zhang SX, Trinh M, Iyer D, Merlo X, Lough JW, Parmacek MS, Bruneau BG, Schwartz RJ. Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes. J Biol Chem. 2005;280(12):11816-28.
Xu H, Morishima M, Wylie JN, Schwartz RJ, Bruneau BG, Lindsay EA, Baldini A. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development. 2004;131(13):3217-27.
Recent Publications, Jun Wang, MD, PhD
* = Corresponding author(s)
♦ = Invited review/research article
Chen L, Ma Y, Yu W, Schwartz RJ, Qian L, Wang J: Conditional ablation of Ezh2 in murine hearts reveals its essential roles in endocardial cushion formation, cardiomyocyte proliferation and survival. PLoS ONE. 2012;7(2):e31005.
Kim EY, Chen L, Ma Y, Yu W, Chang J, Moskowitz IP, Wang J: Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. Journal of Molecular and Cellular Cardiology. 2012: 52(3):638-49.
Kim EY, Chen L, Ma Y, Yu W, Chang J, Moskowitz IP, Wang J: Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects. PLoS One. 2011;6(6):e20803.
♦ Wang J*, Chen L, Wen S, Zhu H, Yu W, Moskowitz IP, Shaw GM, Finnell RH, Schwartz RJ*: Defective sumoylation pathway directs congenital heart disease. Birth Defects Research, A Clinical Molecular Teratology. 2011;91(6):468-76.
Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE: Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. Proceedings of the National Academy of Sciences USA. 2011;108(10):4006-11.
♦ Wang J: Cardiac function and disease: emerging role of small ubiquitin-related modifier. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2011;3(4):446-57.
♦ Wang J, Schwartz RJ: Sumoylation and regulation of cardiac gene expression. Circulation Research. 2010;107(1):19-29.
♦ Wang J: SUMO conjugation and cardiovascular development. Frontiers in Bioscience. 2009;14:1219-29.
Wang J*, Zhang H, Iyer D, Feng XH, Schwartz RJ : Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. Journal of Biological Chemistry. 2008;283(34):23235-43.
Majalahti T, Suo-Palosaari M, Sarman B, Hautala N, Pikkarainen S, Tokola H, Vuolteenaho O, Wang J, Paradis P, Nemer M, Ruskoaho H: Cardiac BNP gene activation by angiotensin II in vivo. Molecular and Cellular Endocrinology. 2007;273(1-2):59-67.
Zhu L, Harutyunyan KG, Peng JL, Wang J, Schwartz RJ, Belmont JW: Identification of a novel role of ZIC3 in regulating cardiac development. Human Molecular Genetics. 2007;16(14):1649-60.
Wang J, Li A, Wang Z, Feng X, Olson EN, Schwartz RJ: Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts. Molecular and Cellular Biology. 2007;27(2):622-632.
Wang J, Paradis P, Aries A, Komati H, Lefebvre C, Wang H, Nemer M: Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4. Molecular and Cellular Biology. 2005;25(22):9829-44.
Wang J, Feng XH, Schwartz RJ: SUMO-1 modification activated GATA4-dependent cardiogenic gene activity. Journal of Biological Chemistry. 2004;279(47):49091-8.
Contact Information and Location
Stem Cell Engineering
Texas Heart Institute
6770 Bertner Avenue, MC 2-255
Houston, TX 77030
Robert J. Schwartz, PhD
Jun Wang, MD, PhD
Updated July 2014