miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway

Marta Diez-Cuñado; Ke Wei; Paul J Bushway; Mano R Maurya; Ranjan Perera; Shankar Subramaniam; Pilar Ruiz-Lozano; Mark Mercola

doi:10.1016/j.celrep.2018.04.049

miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway

Cell Rep. 2018 May 15;23(7):2168-2174. doi: 10.1016/j.celrep.2018.04.049.

Authors

Marta Diez-Cuñado¹, Ke Wei², Paul J Bushway³, Mano R Maurya⁴, Ranjan Perera¹, Shankar Subramaniam⁵, Pilar Ruiz-Lozano⁶, Mark Mercola⁷

Affiliations

¹ Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
² Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
³ Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA; Computer Science and Engineering, Cellular and Molecular Medicine, and Graduate Program in Bioinformatics, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Stanford Cardiovascular Institute and Department of Medicine, Stanford, CA 94305, USA; Regencor, Inc., Los Altos, CA 92044, USA. Electronic address: pilar@regencor.com.
⁷ Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Stanford Cardiovascular Institute and Department of Medicine, Stanford, CA 94305, USA. Electronic address: mmercola@stanford.edu.

Abstract

Understanding the mechanisms that control human cardiomyocyte proliferation might be applicable to regenerative medicine. We screened a whole genome collection of human miRNAs, identifying 96 to be capable of increasing proliferation (DNA synthesis and cytokinesis) of human iPSC-derived cardiomyocytes. Chemical screening and computational approaches indicated that most of these miRNAs (67) target different components of the Hippo pathway and that their activity depends on the nuclear translocation of the Hippo transcriptional effector YAP. 53 of the 67 miRNAs are present in human iPSC cardiomyocytes, yet anti-miRNA screening revealed that none are individually essential for basal proliferation of hiPSC cardiomyocytes despite the importance of YAP for proliferation. We propose a model in which multiple endogenous miRNAs redundantly suppress Hippo signaling to sustain the cell cycle of immature cardiomyocytes.

Keywords: Hippo pathway; human cardiomyocytes; iPSCs; microRNAs; proliferation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Division / drug effects
Cell Proliferation / drug effects
Culture Media, Conditioned / pharmacology
DNA / biosynthesis
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / metabolism
MicroRNAs / genetics
MicroRNAs / metabolism*
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism*
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction*

Substances

Culture Media, Conditioned
MicroRNAs
DNA
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding