Insulin-like growth factor promotes cardiac lineage induction in vitro by selective expansion of early mesoderm.
A thorough understanding of the developmental signals that direct pluripotent stem cells (PSCs) toward a cardiac fate is essential for translational applications in disease modeling and therapy. We screened a panel of 44 cytokines/signaling molecules for their ability to enhance Nkx2.5(+) cardiac progenitor cell (CPC) formation during in vitro embryonic stem cell (ESC) differentiation. Treatment of murine ESCs with insulin or insulin-like growth factors (IGF1/2) during early differentiation increased mesodermal cell proliferation and, consequently, CPC formation. Furthermore, we show that downstream mediators of IGF signaling (e.g., phospho-Akt and mTOR) are required for this effect. These data support a novel role for IGF family ligands to expand the developing mesoderm and promote cardiac differentiation. Insulin or IGF treatment could provide an effective strategy to increase the PSC-based generation of CPCs and cardiomyocytes for applications in regenerative medicine.
Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Laboratory of Experimental Cardiology, Department of Cardiology, Heart Center Leiden, Leiden University Medical Center, Leiden, The Netherlands.
Marc C
MC
Engels
Kuppusamy
K
Rajarajan
Rebecca
R
Feistritzer
Arun
A
Sharma
Ulrik B
UB
Nielsen
Martin J
MJ
Schalij
Antoine A F
AA
de Vries
Daniël A
DA
Pijnappels
Sean M
SM
Wu
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000378:metabolism; D005326:Fetal Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007328:Insulin; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000098908:Brachyury Protein
D005326:Fetal Proteins; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020825:T-Box Domain Proteins; D058570:TOR Serine-Threonine Kinases; D000098908:Brachyury Protein
Akt; Cardiac differentiation; Cardiac progenitor cell; Cardiomyocyte; Development; Embryonic stem cell; In vitro screening; Insulin; Insulin-like growth factor; Mesoderm