The Kühn Lab

The Self Healing Heart
The Self-Healing Heart

Researchers in Pittsburgh are regenerating pediatric heart tissue, potentially leading to novel approaches for the treatment of heart failure.

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In Pursuit of the Self-Healing Heart

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 pioneering work has already provided insights into the growth mechanisms of these cells. The Kühn Lab’s long-term goal is to lead to 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:

  • How do cardiomyocytes stop dividing?
  • How do differentiated cardiomyocytes re-enter the cell division cycle?
  • If cardiomyocyte regeneration can be stimulated, how can this be controlled? The answers may ultimately lead to regenerative therapies for heart failure.

Areas of Focus

The Kühn Lab within the Richard King Mellon Institute for Pediatric Research conducts pioneering 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.


Inducing Cardiomyocyte Proliferation

Inducing Cardiomyocyte ProliferationThe 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.


Mechanisms of Myocardial Growth and Regeneration

The Kühn Lab is exploring the signals that promote cardiomyocyte cell cycle entry and division. 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


Translational Research

The Kühn Lab are currently working to characterize cardiomyocyte proliferation in children and adults with heart failure.

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.

Lab Team & Contact Information

Bernhard Kühn, MD

Principal Investigator
bernhard.kuhn2@chp.edu
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Lu Han, PhD
Post-Doctoral Associate
luhan@pitt.edu

Honghai Liu, PhD
Post-Doctoral Associate
physhhliu@gmail.com

Niyatie Ammanamanchi, MS
Lab Manager and Research Technician
niyatie.ammanamanchi@chp.edu

Jocelyn Mich-Basso, BS, MT
Lab Manager and Research Technician
jocelyn.basso@chp.edu

Kathryn C. (KC) Little, MA, RN, CCRC
Research Nurse Coordinator
kathryn.little@chp.edu

Contact Us

The Kühn Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 8127
4401 Penn Avenue
Pittsburgh, PA 15224
412-692-9909

News, Presentations, & Achievements

2018

Lab Activities and Achievements

  • Dr. Bernhard Kühn was awarded the Aging Institute of UPMC Seed Grant Program for his project, “A function for B-type lamins in nuclear pore insertion impacts heart repair and regeneration.”

2017

Lab Activities and Achievements

  • Honghai Liu, PhD, received the Children’s Research Advisory Committee grant to fund his research project, Repression of Epithelial Cell Transforming 2 Induces Binucleation of Cardiomyocytes.

Presentations at Scientific Meetings

  • Keystone Symposia and Cellular Biology - Molecular Mechanisms of Heart Development (X7), Keystone, Colo.
    • Honghai Liu, PhD, presented the poster “Repression of Epithelial Cell Transforming 2 Induces Binucleation of Cardiomyocytes.”
    • Abha Bais, PhD, and Niyatie Ammanamanchi, MS, presented the poster “A Transcriptional Map of Human Primary Single Cardiomyocytes.”
  • At the Society for Cardiovascular Magnetic Resonance, 20th Annual Scientific Sessions in Washington, D.C., Yijen Wu, PhD, presented her poster, entitled “Strain Derived from Tagging MRI Is More Sensitive Than Ejection Fraction for Detecting Functional Effects of Myocardial Regeneration.”
  • American Heart Association Fellows Research Day in Pittsburgh, Pa.
    • Krithika Rao, PhD, won the 3rd prize in Basic Science category for her poster presentation, “Ligands of G Protein-coupled Receptors Control Cell Cycle Activity in Neonatal Cardiomyocytes by Modulating Hippo Pathway Signaling.”
    • Honghai Liu, PhD, gave a platform presentation, entitled “ Expression of Epithelial Cell Transforming 2 Induces Bi- and Multi-nucleation of Cardiomyocytes in Mice and Humans.”
    • Balakrishnan Ganapathy, MS, gave a platform presentation, entitled “Strain Derived from Tagging MRI is More Sensitive than Ejection Fraction for Detecting Functional Effects of Myocardial Regeneration.”
    • Abha Bais, gave the platform presentation, “A Transcriptional Map of Human Cardiomyocyte Differentiation at the Single Cell Level.”
    • Christopher Lewarchik, PhD, presented the poster, “Cycling Cardiomyocytes Exhibit Altered Calcium Release.”
    • Niyatie Ammanamanchi, MS, presented the poster, “Lamin B2 Controls Nuclear Envelope Permeability and Can be Used to Regulate Cardiomyocyte Regeneration.”

2016

Presentations at Scientific Meetings

  • Abha Bais, PhD, and Niyatie Ammanamanchi, MS, presented the poster, “ Transcriptional Map of Human Cardiomyocyte Differentiation at the Single-cell Level,” at the American Heart Association Scientific Sessions in New Orleans.
  • Rangos Research Symposium
    • Balakrishnan Ganapathy, MS, gave a platform presentation about the molecular mechanisms by which cardiomyocytes proliferate using RNA-Seq-based single cell transcriptional analysis.
    • Niyatie Ammanamanchi, MS, presented a poster detailing her results from human RNA-seq based single cell transcriptional analysis.
    • Honghai Liu, PhD, presented his poster about the cellular and molecular mechanisms by which cardiomyocytes binucleate.
  • Honghai Liu, PhD, gave a platform presentation about the cellular and molecular mechanisms by which cardiomyocytes binucleate at the Weinstein Conference in North Carolina.

2015

News and Announcements

Lab Activities and Achievements

  • Honghai Liu, PhD, named finalist for best presentation at Fellows' Research Day, Rangos Research Center.
  • Bernhard Kühn, MD, named one of six members of a new international collaborative network funded by a 5-year grant from Fondation Leducq, to pursue heart regeneration through cardiomyocyte division.
  • Children's Hospital of Pittsburgh Foundation provided a 2-year grant, the Functional Genomics Discovery Award to Dr. Kühn for his collaborative work with Dennis Kostka, PhD.

Presentations at Scientific Meetings

  • Bernhard Kühn, MD, was an invited presenter at the American Heart Association Scientific Sessions in Orlando, Fla.
  • Bernhard Kühn, MD, made a lab research presentation at the Molecular Medicine Research Seminars, Rangos Research Center, UPMC Children's Hospital of Pittsburgh.

2014

News and Announcements

Presentations at Scientific Meetings

  • Bernhard Kühn, MD, delivered a Grand Rounds presentation at Cincinnati Children’s Hospital.
  • Bernhard Kühn, MD, was an invited lecturer at Victor Chang Research Institute in Sydney, Australia.
  • Brian Polizzotti, PhD, gave a moderated poster presentation at the meeting of the American College of Cardiology in Washington, D.C.
  • Sangita Choudhury, PhD, received a Career Development Award from the Office of Faculty Development at Boston Children’s Hospital.
  • Bala Ganapathy, MS, presented his poster about stimulating cardiomyocyte regeneration in neonatal mice at the Basic Research Meeting of the American Heart Association in Las Vegas.

Publications

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
2017 Feb

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
PLOS ONE
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
Nature Protocols
2016 Mar

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
2014 Sep

Muscling Up the Heart - A Preadolescent Cardiomyocyte Proliferation Contributes to Heart Growth
CH Zhang, B Kühn
Circulation Research
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
Circulation
2014 Jul 1

Signalling between microvascular endothelium and cardiomyocytes through neuregulin (PDF)
EM Parodi, B Kühn
Cardiovasc Res
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
PNAS
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
PLoS ONE
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
Circulation
2010 Mar 2

Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury (PDF) 
K Bersell, S Arab, B Haring, B Kühn
Cell
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.
Nat Med
2007 Aug

Opportunities to Join

We’d Like to Hear From You!

The Kühn Lab is always looking for talented, curious, and driven researchers to join our team.

Postdoctoral Associates

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.

Graduate Students

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.

Undergraduate Students

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.