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Biomedical Research
|
Volume 29
Page 48
allied
academies
CARDIOLOGY AND CARDIOVASCULAR MEDICINE
STEM CELLS AND REGENERATIVE MEDICINE
&
International Conference on
International Conference on
J u n e 1 8 - 1 9 , 2 0 1 8 | O s a k a , J a p a n
Joint Event on
NOVEL APPROACHES FOR ENDOGENOUS HEART REPAIR
Tamer M A Mohamed
University of Manchester, UK
Background:
Heart failure is often caused by loss of cardiac cells that are unable to re-enter the cell cycle for regeneration.
Numerous attempts to identify such cell cycle regulators that could induce cell division of cardiomyocytes, or other cell
types, have resulted in nuclear division (karyokinesis), but inefficient cleavage into two distinct daughter cells (cytokinesis)
and subsequent survival. Such strategies stimulate cell cycle markers in no more than 1% of cardiomyocytes, limiting their
utility.
Methods and results:
Here, we took a combinatorial approach to screen for cell cycle factors and conditions that could
recapitulate the fetal state of cardiomyocyte division. We found that ectopic introduction of the Cdk1/CyclinB1 and the
Cdk4/CyclinD1 complexes promoted cell division in at least 15% of mouse and human cardiomyocytes
in vitro
. Rigorous
assessment of cell division
in vivo
with the cardiac specific (-MHC) Cre-recombinase dependent Mosaic Analysis with
Double Markers (MADM) lineage tracing system revealed similar efficiency in adult mouse hearts, leading to cardiac
regeneration upon delivery of cell cycle regulators immediately after myocardial infarction and even one week after injury.
This ability of cardiac regeneration resulted in significant improvement in cardiac function following acute or subacute
myocardial infarction. Intra-myocardial injection of adenoviruses encoding the 4 cell cycle gene either injected at the time
of the infarction or one week following myocardial infarction resulted in significant improvement in cardiac function as
assessed by echocardiography and MRI compared to animals received control virus. Furthermore, chemical inhibition of
Tgf and Wee1 made CDK1 and cyclin B dispensable, simplifying the minimal genetic requirement.
Conclusion:
These findings reveal a discrete combination of genes that can unlock the proliferative potential in cells that
had permanently exited the cell cycle.
tamer.mohamed@manchester.ac.ukBiomed Res 2018, Volume 29 | DOI: 10.4066/biomedicalresearch-C2-006