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Researchers in Pittsburgh are regenerating pediatric heart tissue, potentially leading to novel approaches for the treatment of heart failure.
While much is understood about the mechanisms of the life-sustaining pump known as the human heart, when it is examined on the cellular and molecular level many mysteries remain. Unraveling the secrets of what makes heart muscle cells different from most others in the human body is the passion of Bernhard Kühn, MD, whose laboratory resides within the Richard King Mellon Institute for Pediatric Research. Notably, these specialized contractile cells, called cardiomyocytes, are exceptional in that they lack the ability to replicate and proliferate, processes that are necessary to repair tissue damage and restore normal function.
Our innovative work has already provided insight into the growth mechanisms of these cells. The Kühn Lab’s long-term goal is to regenerate human hearts. This involves developing therapies that can help the heart muscle, the myocardium, to heal itself – to recover from a heart attack, or to help it restore a congenital heart defect to normal cardiac function without requiring surgery.
As part of the Institute for Pediatric Research, the Kühn Lab coordinates with the Heart Institute of UPMC Children’s Hospital of Pittsburgh and the McGowan Institute for Regenerative Medicine to advance its work from the research lab to clinical care.
Through its initiatives, the Kühn Lab addresses these important biological questions:
The Kühn Lab within the Richard King Mellon Institute for Pediatric Research conducts cutting-edge investigations into the cellular and molecular mechanisms of the heart muscle in search of a cure for heart failure. The long-term objective is to provide cellular and molecular targets for therapeutic treatment of heart failure and congenital heart disease.
We know that natural cardiomyocyte proliferation is not sufficient to regenerate heart muscle defects in babies and children with congenital heart disease or in adults after a heart attack. Heart failure can be the result.
By focusing on the mechanisms of growth and regeneration of the myocardium, Dr. Kühn’s research has already led to important discoveries. His work has shown that administration of two naturally occurring peptides, periostin and neuregulin, can stimulate cardiomyocytes to proliferate and, in animals, repair myocardial defects and restore cardiac function.
Members of the Kühn Lab team are focused on three initial areas:
The Kühn Lab team are taking these findings and turning them into new and novel therapies for healing the hearts of children and adults.
The Kühn Lab has discovered that cell cycle re-entry and division of cardiomyocytes is induced by periostin peptide, a component of the extracellular matrix, and neuregulin 1 (NRG1), a growth factor. After experimentally inducing myocardial infarctions, we have shown that the administration of recombinant periostin peptide or NGR1 enhances cardiomyocyte cycling, reduces infarct size, and improves myocardial function. Using an animal model to mimic heart failure in babies and children, we are currently testing the therapeutic benefits of NGR1 administration.
We have demonstrated that a sub-population of differentiated cardiomyocytes has proliferative potential and responds to periostin peptide and NGR1 with cell cycle re-entry.
Regeneration is an important mechanism of tissue homeostasis in multicellular organisms, and the limited ability of the mammalian heart to regenerate is remarkable. Many mammalian tissues, such as blood and skin, regenerate after injury, relying on undifferentiated stem cells.
Heart tissue, like other tissues with limited regenerative capacity, is largely comprised of terminally differentiated cells. This means that they do not divide. However, some cardiomyocytes can re-enter the cell division cycle under certain conditions. For example, cardiomyocyte cell cycle activity in the region bordering a myocardial infarction increases transiently. Although this increase is not sufficient for effective regeneration, it suggests that some cardiomyocytes may proliferate in response to extracellular signals present in the infarct border zone.
The Kühn Lab is exploring the signals that promote cardiomyocyte cell cycle entry and division with the hope of identifying specific factors that can become leads for new medications
Stimulating cardiomyocyte proliferation with periostin peptide or with neuregulin 1 shows great potential for repairing the mammalian heart after injury due to myocardial infarction, or to repair congenital heart defects, such as hypoplastic left heart syndrome.
As a step toward this goal, researchers in the Kühn Lab are currently working to characterize cardiomyocyte proliferation in children and adults with heart failure.
We have demonstrated that cardiomyocyte proliferation contributes to heart growth in babies and children. This raises the possibility to target this process with new regenerative therapies. One of our regeneration factors, neuregulin, is currently in clinical phase 2 testing in adult heart failure patients. We do not have financial interests in the development of neuregulin as a therapy and look forward to advancing toward clinical trials in children. The significance and promise of research on cardiomyocyte regeneration for developing new heart failure therapies for babies and infants was recognized by a working group of the National Heart Lung and Blood Institute in 2013.
Lu Han, PhD
Research Assistant Professor
Honghai Liu, PhD
Jessie Yester, MD, PhD
Anita Saraf, MD, PhD
Assistant Professor, Heart Institute
Niyatie Ammanamanchi, MS
Lab Manager and Research Technician
Jocelyn Mich-Basso, BS, MT
Lab Manager and Research Technician
Dawn Thomas RN, MSN, CPN
Research Nurse Coordinator
The Kühn Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 8127
4401 Penn Avenue
Pittsburgh, PA 15224
Cardiology Fellow Jessie Yester, MD, won the 2019 Sang Park award. She will use it to advance heart regeneration research in our patients with congenital heart disease.
Polyploid cardiomyocytes: Implications for heart regeneration
Anna Kirillova, Lu Han, Honghai Liu, Bernhard Kuhn
Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot
Samar R.El Khoudary, AnthonyFabio, Jessie W. Yester, Matthew L. Steinhauser, Adam B. Christopher, Frank Gyngard, Phillip S. Adams, Victor O. Morell, Melita Viegas, Jose P. DaSilva, Luciana F. DaSilva, Mario Castro-Medina, Andrew McCormick, Miguel Reyes-Mugica, Michelle Barlas, Honghai Liu, Dawn Thomas, Niyatie Ammanamanchi, Bernhard Kuhn
International Journal of Cardiology
2021 July 12
Use of stable isotope-tagged thymidine and multi-isotope imaging mass spectrometry (MIMS) for quantification of human cardiomyocyte division
Jessie W. Yester, Honghai Liu, Frank Gyngard, Niyatie Ammanamanchi, Katherine C. Little, Dawn Thomas, Mara L.G. Sullivan, Sean Lal, Matthew L. Steinhauser, and Bernhard Kühn
2021 Feb 24
Lamin B2 Levels Regulate Polyploidization of Cardiomyocyte Nuclei and Myocardial Regeneration
Lu Han, Sangita Choudhury, Jocelyn D. Mich Basso, Niyatie Ammanamanchi, Balakrishnan Ganapathy, Sangita Suresh, Mugdha Khaladkar, Jennifer Singh, Rene Maehr, Daniel A.Zuppo, Junhyong Kim, James H. Eberwine, Samuel K. Wyman, Yijen L.Wu, Bernhard Kühn
2020 April 6
Control of Cytokinesis by β-adrenergic Receptors Indicates an Approach for Regulating Cardiomyocyte Endowment
Liu H, Zhang CH, Ammanamanchi N, Suresh S, Lewarchik C, Rao K, Uys GM, Han L, Abrial M, Yimlamai D, Ganapathy B, Guillermier C, Chen N, Khaladkar M, Spaethling J, Eberwine JH, Kim J, Walsh S, Choudhury S, Little K, Francis K, Sharma M, Viegas M, Bais A, Kostka D, Ding J, Bar-Joseph Z, Wu Y, Yechoor V, Moulik M, Johnson J, Weinberg J, Reyes-Múgica M, Steinhauser ML, Kühn B
Science Translational Medicine
2019 Oct 9
Mechanisms of Cardiomyocyte Proliferation and Differentiation in Development and Regeneration
JW Yester, B Kühn
Current Cardiology Reports
Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth
B. Ganapathy, N. Nandhagopal, B. Polizzotti, D. Bennett, A. Asan, Y. Wu, B. Kühn
2016 May 13
A cryoinjury model in neonatal mice for cardiac translational and regeneration research
BD Polizzotti, B Ganapathy, BJ Haubner, JM Penninger, B. Kühn
Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window (PDF)
BD Polizzotti, B Ganapathy, S Walsh, S Choudhury, N Ammanamanchi, DG Bennett, CG dos Remedios, BJ Haubner, JM Penninger, B. Kühn
Science Translational Medicine
2015 Apr 1
Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation (PDF)
SE Senyo, RT Lee, B Kühn
Stem Cell Research
Muscling Up the Heart - A Preadolescent Cardiomyocyte Proliferation Contributes to Heart Growth
CH Zhang, B Kühn
2014 Sep 26
New mechanistic and therapeutic targets for pediatric heart failure: report from a national heart, lung, and blood institute working group (PDF)
KM Burns, BJ Byrne, BD Gelb, B Kühn, LA Leinwand, S Mital, GD Pearson, M Rodefeld, JW Rossano, BL Stauffer, MD Taylor, JA Towbin, AN Redington
2014 Jul 1
Signalling between microvascular endothelium and cardiomyocytes through neuregulin (PDF)
EM Parodi, B Kühn
2014 May 1 (Epub 2014 Jan 29)
Moderate and high amounts of tamoxifen in α-MHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death (PDF)
K Bersell, S Choudhury, M Mollova, BD Polizzotti, B Ganapathy, S Walsh, B Wadugu, S Arab, B Kühn
Disease Models & Mech
2013 Nov (posted online 2013 Aug 7)
Cardiomyocyte proliferation contributes to heart growth in young humans (PDF)
M Mollova, K Bersell, S Walsh, J Savla, LT Das, SY Park, LE Silberstein, CG Dos Remedios, D Graham, S Colan, B Kühn
2013 Jan 22
Intrapericardial delivery of gelfoam enables the targeted delivery of periostin peptide after myocardial infarction by inducing fibrin clot formation (PDF)
BD Polizzotti, S Arab, B Kühn
2012 May 10
The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation (PDF)
B Wadugu, B Kühn B
Am J Physiol Heart Circ Physiol
2012 Mar 16
Taking the load off: Nuclear remodeling after mechanically supporting the failing human heart (PDF)
C Murry, B Kühn
2010 Mar 2
Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury (PDF)
K Bersell, S Arab, B Haring, B Kühn
2009 Jul 24
Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair (PDF)
B Kühn, F Del Monte, RJ Hajjar, YS Chang, D Lebeche, S Arab S, et al.
The Kühn Lab is always looking for talented, curious, and driven researchers to join our team.
The Kuhn lab is seeking a qualified candidate for a Research Scientist position. The primary role in the laboratory will be to design, conduct, and analyze studies with a focus on cardiac regeneration. The studies will explore the terminal differentiation of heart muscle cells. The incumbent will be an active collaborator with the lab Research Director and the Principal Investigator in the development and implementation of this research and will facilitate and coordinate all aspects of this project.
Specific duties include developing and testing proposed methodologies and experimental protocols. Additionally, this individual will be expected to apply microscopy methods of the lab, as well as, be responsible for cardiomyocyte culture methods and mammalian specimen genetics. Experience in molecular biology, biochemistry, or cellular immunology is preferred.
This position is located at UPMC Children’s Hospital of Pittsburgh in Lawrenceville.
PA Child Abuse History Clearance, PA State Police Criminal Record Check, and FBI Criminal Record Check will be required prior to the start of employment. Also, a current TB test will be required as a condition of employment. EEO/AA/M/F/Vets/Disabled.
Doctoral degree (or professional degree/specialized technical training) required with 3-5 years of research experience in a related field of study. Experience in molecular biology, biochemistry, or cellular immunology is preferred.
We are searching for applicants with excellent academic performance and first-author publications. We promote high research standards, foster teamwork, and provide supportive mentors hip. We encourage and support our post-docs to secure fellowship grants. Most projects are multi-disciplinary and involve experts from diverse fields of research. Specific research approaches include: transcriptional profiling of single cardiomyocytes from animals and humans; myocardial regeneration in neonatal mice; microscopy of cardiomyocytes in culture and in the intact heart for measurements of structure and function; directing terminal differentiation of ES- and iPS-cell derived cardiomyocytes.
We welcome graduate students for rotations and to do their research thesis. We are looking for applicants with previous wet-lab experience. Although we do not offer thesis projects that are purely theoretical, students with interest and background in bioinformatics, computational biology, or mathematics are encouraged to apply.
We welcome undergraduate students from all departments and encourage first- and second-year students who are interested in a thesis project to contact us. Undergraduate students will be encouraged to stay with our lab until their graduation in order to accomplish a research project. The expected time commitment during the academic year is 10-15 hours per week, ideally in blocks of more than 3-5 hours at a time.
For inquiries regarding available positions, please contact Dr. Kühn via email.
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