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OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
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NAME: Johannes (Jop) van Berlo
eRA COMMONS USER NAME (credential, e.g., agency login): vanberloj
POSITION TITLE: Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
DEGREE
(if
applicable)
University Maastricht, the Netherlands
University Maastricht/University Hospital Maastricht,
the Netherlands
University Hospital Maastricht, the Netherlands
M.D.
Children’s Hospital Medical Center, Cincinnati,OH
Completion
Date
MM/YYYY
FIELD OF STUDY
Medicine
Resident
1995-2001
2002-2004,
awarded 2006
2004-2007
Fellow
2007-2013
Cardiac Biology
Ph.D.
Medicine/Cardiology
Medicine/Cardiology
A. Personal Statement
My lab studies the mechanisms that regulate cardiac regeneration. The ultimate goal of this research is to
identify novel therapeutic strategies to enhance cardiac regeneration in patients. We use animal models to
study endogenous cardiac regeneration and have developed targeted mouse models to perform genetic
lineage tracing of cardiac progenitor cells.
Cardiac progenitor cells are attractive targets for therapeutic regeneration since they have multi-lineage
potential. Although previous studies have suggested that different cardiac progenitor cells can all differentiate
into the lineages that build the heart (cardiomyocytes, endothelial and smooth muscle cells), to what extent
endogenous progenitors are capable of doing this is an open question. We began tackling this question by
generating targeted knock-in mice for the marker gene c-kit. However, we noticed low numbers of
cardiomyocytes coming from c-kit expressing cells. We currently have a manuscript submitted in which we
discovered that Doxorubicin treatment stimulates c-kit+ cells to become cardiomyocytes. We furthermore
identified p53 as a critical regulator of this enhanced cardiomyocyte differentiation ability.
A second approach we are taking to regenerate the heart is to enhance cardiomyocyte proliferation. The main
factor that limits regeneration of the adult heart is the inability to generate more cardiomyocytes. Zebrafish and
newt retain the ability to regenerate their hearts due to re-activation of cardiomyocyte proliferation in response
to injury. Interestingly, the neonatal mouse heart is able to completely regenerate after injury, but only as long
as cardiomyocytes are proliferative. The underlying mechanisms that regulate the permanent exit from cell
cycle of cardiomyocytes soon after birth are not understood. We have performed a genome-wide, highthroughput, high-content screen to identify novel regulators of cardiomyocyte proliferation, and are currently
studying a number of genes for their effect on cardiomyocyte proliferation.
B. Positions and Honors
Positions
01/02 – 09/04
09/04 – 03/05
04/05 – 03/07
Ph.D. student in Medicine, University Maastricht and University Hospital Maastricht,
Department of Cardiology, Maastricht, the Netherlands
Resident in Cardiology, University Hospital Maastricht, Department of Cardiology,
Maastricht, the Netherlands
Resident in Cardiology, University Hospital Maastricht, Department of Internal Medicine,
Maastricht, the Netherlands
04/07 – 07/13
07/13 – present
Postdoctoral Fellow, Children’s Hospital Medical Center Cincinnati, Department of
Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati OH
Mentor:
Dr. J.D. Molkentin
Assistant Professor, University of Minnesota, Lillehei Heart Institute, Department of
Medicine, Minneapolis, MN
Honors and Awards
2002
Pre-doctoral fellowship Netherlands Heart Foundation.
2004
Winner, poster prize 40th Anniversary Scientific Sessions of the Netherlands Heart
Foundation, Utrecht, the Netherlands
2009
Winner, University of Cincinnati Research Council Postdoctoral Research Fellowship
2010
Postdoctoral fellowship American Heart Association, Great Rivers Affiliate
2011
Winner, ISHR International Poster Competition from the International Society for Heart
Research
2012
NIH Pathway to Independence Award (K99/R00)
2013
Finalist, Melvin L. Marcus Young Investigator Award from the American Heart
Association
2016
Early Career Committee, Basic Cardiovascular Sciences council American Heart
Association
Professional Memberships
2009 – present
American Heart Association, council on basic cardiovascular sciences
2011 – present
International Society for Heart Research
2016 – present
American Physiological Society
C. Contribution to Science
1. Genetic Lineage Tracing of Cardiac Progenitor Cells
Although the existence of cardiac progenitor cells was first discovered and described over a decade ago,
up until a year ago most of the data on the importance of CPCs for cardiac regeneration was derived from
cultured CPCs. These cultured CPCs showed ability to differentiate toward various cardiac lineages under
certain culture conditions and upon injection into the heart after myocardial infarction showed the ability to
contribute cardiomyocytes to the regenerating heart. However, to what extent endogenous CPCs (without
undergoing cell culture, which is well-known to change the phenotype/ability of cells) could contribute
cardiomyocytes to the developing or aging heart, or after myocardial injury was not known. To determine
the importance of eCPCs for cardiac development and to assess the numbers of eCPC derived
cardiomyocytes, we targeted the murine Kit locus to generate both constitutively active and tamoxifen
inducible Cre recombinase mouse lines to allow genetic lineage tracing of c-kit expressing cells, the main
result of the NIH funded K99/R00 Pathway to Independence award.
1) Yellamilli A and van Berlo JH. The Role of Cardiac Side Population Cells in Cardiac Regeneration.
Front Cell Dev Biol. 2016 Sep 13;4:102. PMID: 27679798
2) Van Berlo JH and Molkentin JD. Most of the Dust Has Settled: cKit+ Progenitor Cells Are an Irrelevant
Source of Cardiac Myocytes In Vivo. Circ Res. 2016 Jan 8;118(1):17-9. PMID: 26837741
3) Van Berlo JH and Molkentin JD. An emerging consensus on cardiac regeneration. Nature Medicine
2014 Dec 4;20(12):1386-93. PMID: 25473919
4) Van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SCJ, Middleton RC, Marbán E,
Molkentin JD. C-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014 May
15;509(7500):337-41. PMID: 24805242
2. Gata Transcription Factors Mediate Cardiac Hypertrophy and Propensity to Heart Failure
My postdoctoral research, which was funded by an AHA postdoctoral fellowship, defined the roles of Gata4
and Gata6 transcription factors for the development of cardiac hypertrophy and heart failure. We were the
first to define the role of Gata6 in the adult heart by using a combination of genetic deletion and
complementation studies under normal baseline conditions and after different stimuli to induce cardiac
stress. Furthermore, we made a direct comparison between Gata4 and Gata6 and were able to show that
although the proteins have very similar actions, they are not completely redundant. Finally, we generated a
targeted ‘knock-in’ mutant where Gata4 could no longer be phosphorylated in response to MAPK
activation. This blunted the transactivation potential of Gata4, thereby diminishing the overall level of
cardiac hypertrophy attained in response to different stress stimuli.
1) Van Berlo JH, Aronow BJ, Molkentin JD. Parsing the roles of the transcription factors GATA-4 and
GATA-6 in the adult cardiac hypertrophic response. PLoS One 2013 Dec 31;8(12):e84591. PMID:
24391969
2) Van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and
remodeling of the heart. J Clin Invest. 2013 Jan 2;123(1):37-45. PMID: 23281408
3) Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental
concepts and new players. Nat Rev Mol Cell Biol. 2013 Jan;14(1):38-48. PMID: 23258295
4) Van Berlo JH, Elrod JW, Aronow BJ, Pu WT, Molkentin JD. Serine 105 phosphorylation of transcription
factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo. Proc Natl Acad Sci U.S.A.
2011 Jul 26;108(30):12331-6. PMID: 21746915
5) Van Berlo JH, Elrod JW, van den Hoogenhof MM, York AJ, Aronow BJ, Duncan SA, Molkentin JD. The
transcription factor GATA-6 regulates pathological cardiac hypertrophy. Circ Res. 2010 Oct
15;107(8):1032-40. PMID: 20705924
3. High Risk of Sudden Cardiac Death in Lamin A/C Gene Mutation Carriers is likely due to primary
cardiac fibrosis and may be prevented by ICD implantation
My PhD research focused on the role of inherited cardiomyopathies due to mutations in the LMNA gene.
Patients that carry Lamin A/C mutations giving rise to either pure dilated cardiomyopathy, or EmeryDreifuss muscular dystrophy, or limb-girdle muscular dystrophy appeared to have an increased risk of
sudden cardiac death that could not be prevented by implantation of a pacemaker. These findings
suggested an implantable converter defibrillator (ICD) might be required instead of a pacemaker. We
performed a small study in 19 patients that were in need of pacemaker implantation, but instead implanted
an ICD with pacemaker capabilities. Over a 3-year follow up, we observed ICD discharge in 6 patients for
ventricular fibrillation and in 2 patients for ventricular tachycardia. Importantly, some patients received ICD
discharges when their cardiac function was still normal, suggesting to us these patients might have a
specific substrate to increase their risk of tachycardias. Mechanistically, we identified fibrosis in cardiac
biopsies of gene mutation carriers before they displayed cardiac dysfunction, and we were able to show
enhanced fibroblast proliferation and collagen production in LMNA gene deleted fibroblasts due to
sustained transcription factor activation in absence of proper phosphatase functioning. The studies
described here included the first primary prevention trial for a specific genetic form of heart failure and the
option to perform implantation of ICDs for primary prevention of sudden death has since been implemented
in heart failure guidelines.
1) Van Tintelen JP, Tio RA, Kerstjens-Frederikse WS, van Berlo JH, Boven LG, Suurmeijer AJ, White SJ,
den Dunnen JT, te Meerman GJ, Vos YJ, van der Hout AH, Osinga J, van den Berg MP, van
Veldhuisen DJ, Buys CH, Hofstra RM, Pinto YM. Severe myocardial fibrosis caused by a deletion of the
5’ end of the lamin A/C gene. J Am Coll Cardiol. 2007 Jun 26;49(25):2430-9. PMID: 17599607.
2) Meune C, van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden
death in patients with lamin A/C gene mutations. N Engl J Med 2006 Jan 12; 354(2): 209-10. PMID:
16407522.
3) Van Berlo JH, Voncken JW, Kubben N, Broers JLV, Duisters R, van Leeuwen REW, Crijns HJGM,
Ramaekers FCS, Hutchison CJ, Pinto YM. A-type lamins are essential for TGF-1 induced PP2A to
dephosphorylate transcription factors. Hum Mol Genet. 2005 Oct 1;14(19):2839-49. PMID: 16115815.
4) Van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D,
Rossenbacker T, Heidbuchel H, de Visser M, Crijns HJ, Pinto YM. Meta-analysis of clinical
characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of
sudden death? J Mol Med. 2005 Jan;83(1):79-83. PMID: 15551023.
5) van Berlo JH, Duboc D, Pinto YM. Often seen but rarely recognised: cardiac complications of lamin
A/C mutations. Eur Heart J. 2004 May;25(10):812-4. PMID: 15140529
4. Contribution to discovery of Galectin-3 as a biomarker for heart failure
I was part of the research team that performed the studies that led to the discovery of Galectin-3 as a
biomarker for heart failure. We used a rat model with homozygous expression of a transgenic renin gene.
These rats all develop cardiac hypertrophy by 10 weeks of age, but only 40-50% will show signs of heart
failure over the next 6-8 weeks, while the remaining 50-60% of rats remain in a state of compensated
hypertrophy. We used cardiac biopsies at a time when all rats had developed hypertrophy, but none were
in heart failure and performed gene expression studies. These expression profiles were later classified to
eventual development of heart failure (6 rats) or not (8 rats). This allowed us to identify a number of genes
that showed differential expression at this earlier time point when no signs of heart failure were present yet.
Probably the most important discovery from this experiment was the identification of macrophage-produced
galectin-3 as a bio-marker for heart failure. I am still regularly interacting with Dr. Sharma and I am helping
him with writing a proposal for an NIH K award to further study the role of Galectin-3.
1) Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, Andre S, Crijns HJ,
Gabius HJ, Maessen J, Pinto YM. Galectin-3 marks activated macrophages in failure-prone
hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004 Nov 9;110(19):3121-8.
PMID: 15520318.
Complete List of Published Work in MyBibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/johannes.van
berlo.1/bibliography/45984132/public/?sort=date&direction=ascending.
D. Research Support
Ongoing Research Support
1R01HL130072
van Berlo (PI)
12/15/15 – 10/31/20
NIH/NHLBI
Title: Strategic activation of endogenous c-kit+ progenitor cells for cardiac regeneration
The goal is to activate c-kit+ progenitor cells to proliferate and differentiate to enhance their regenerative
potential.
Role: PI
Completed Research Support
4R00HL112852
van Berlo (PI)
4/1/12 – 6/30/16
NIH/NHLBI
Title: Functional relevance of cardiac regeneration by c-kit positive stem cells
The goal is to define the role of c-kit positive stem cells in cardiac renewal and regeneration through genetic
lineage tracing.
Role: PI
07/10 – 03/12
Postdoctoral Fellowship, AHA Great Rivers affiliate, PI