Identification of Chemicals Inducing Cardiomyocyte Proliferation in Developmental Stage–Specific Manner With Pluripotent Stem Cells

• DOI: 10.1161/circgenetics.113.000330
• Publication Date: 2013-10-19T02:07:06Z
• Authors: Hideki Uosaki; Ajit Magadum; Kinya Seo; Hiroyuki Fukushima; Ayako Takeuchi; Yasuaki Nakagawa; Kara White Moyes; Genta Narazaki; Koichiro Kuwahara; Michael Laflamme; Satoshi Matsuoka; Norio Nakatsuji; Kazuwa Nakao; Chulan Kwon; David A. Kass; Felix B. Engel; Jun K. Yamashita
• Keywords: Pluripotent Stem Cells; 0303 health sciences; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Enzyme Activators; Gene Expression; Cell Differentiation; Immunohistochemistry; Cell Line; Enzyme Activation; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; Animals, Newborn; Animals; Humans; Myocytes, Cardiac; Enzyme Inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Extracellular Signal-Regulated MAP Kinases; Embryonic Stem Cells; Cell Proliferation

The proliferation of cardiomyocytes is highly restricted after postnatal maturation, limiting heart regeneration. Elucidation the regulatory machineries for and growth arrest imperative. Chemical biology efficient to dissect molecular mechanisms various cellular events often provides therapeutic potentials. We have been investigating cardiovascular differentiation with pluripotent stem cells. combination cell chemical can provide novel approaches investigate manipulation cardiomyocyte proliferation.To identify chemicals that regulate proliferation, we performed a screening defined library based on mouse cell-derived identified 4 compound groups: inhibitors glycogen synthase kinase-3, p38 mitogen-activated protein kinase, Ca(2+)/calmodulin-dependent kinase II, activators extracellular signal-regulated kinase. Several appropriate combinations synergistically enhanced derived from both human cells, notably up 14-fold increase in cardiomyocytes. also examined effects developmental stages species. Whereas II showed proliferative only early stages, kinase-3 substantially induced re-entry progression cycle neonatal but as well adult cardiomyocytes.Our approach successfully uncovered targets controlling distinct offered potent tool explore chemical-based cardiac regenerative strategies.