Induction of human iPSC-derived cardiomyocyte proliferation revealed by combinatorial screening in high density microbioreactor arrays

Titmarsh, Drew M., Glass, Nick R., Mills, Richard J., Hidalgo, Alejandro, Wolvetang, Ernst J., Porrello, Enzo R., Hudson, James E. and Cooper-White, Justin J. (2016) Induction of human iPSC-derived cardiomyocyte proliferation revealed by combinatorial screening in high density microbioreactor arrays. Scientific Reports, 6 . doi:10.1038/srep24637


Author Titmarsh, Drew M.
Glass, Nick R.
Mills, Richard J.
Hidalgo, Alejandro
Wolvetang, Ernst J.
Porrello, Enzo R.
Hudson, James E.
Cooper-White, Justin J.
Title Induction of human iPSC-derived cardiomyocyte proliferation revealed by combinatorial screening in high density microbioreactor arrays
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-04-21
Year available 2016
Sub-type Article (original research)
DOI 10.1038/srep24637
Open Access Status DOI
Volume 6
Total pages 15
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted abstract
Inducing cardiomyocyte proliferation in post-mitotic adult heart tissue is attracting significant attention as a therapeutic strategy to regenerate the heart after injury. Model animal screens have identified several candidate signalling pathways, however, it remains unclear as to what extent these pathways can be exploited, either individually or in combination, in the human system. The advent of human cardiac cells from directed differentiation of human pluripotent stem cells (hPSCs) now provides the ability to interrogate human cardiac biology in vitro, but it remains difficult with existing culture formats to simply and rapidly elucidate signalling pathway penetrance and interplay. To facilitate high-throughput combinatorial screening of candidate biologicals or factors driving relevant molecular pathways, we developed a high-density microbioreactor array (HDMA) - a microfluidic cell culture array containing 8100 culture chambers. We used HDMAs to combinatorially screen Wnt, Hedgehog, IGF and FGF pathway agonists. The Wnt activator CHIR99021 was identified as the most potent molecular inducer of human cardiomyocyte proliferation, inducing cell cycle activity marked by Ki67, and an increase in cardiomyocyte numbers compared to controls. The combination of human cardiomyocytes with the HDMA provides a versatile and rapid tool for stratifying combinations of factors for heart regeneration.
Keyword Human iPSC-derived cardiomyocyte
Combinatorial screening
High density microbioreactor array
HDMA
Human pluripotent stem cells
HPSCs
Therapeutic strategy
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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