Cardiogenic small molecules that enhance myocardial repair by stem cells.
The clinical success of stem cell therapy for myocardial repair hinges on a better understanding of cardiac fate mechanisms. We have identified small molecules involved in cardiac fate by screening a chemical library for activators of the signature gene Nkx2.5, using a luciferase knockin bacterial artificial chromosome (BAC) in mouse P19CL6 pluripotent stem cells. We describe a family of sulfonyl-hydrazone (Shz) small molecules that can trigger cardiac mRNA and protein expression in a variety of embryonic and adult stem/progenitor cells, including human mobilized peripheral blood mononuclear cells (M-PBMCs). Small-molecule-enhanced M-PBMCs engrafted into the rat heart in proximity to an experimental injury improved cardiac function better than control cells. Recovery of cardiac function correlated with persistence of viable human cells, expressing human-specific cardiac mRNAs and proteins. Shz small molecules are promising starting points for drugs to promote myocardial repair/regeneration by activating cardiac differentiation in M-PBMCs.
Sadek
Hesham
H
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hannack
Britta
B
Choe
Elizabeth
E
Wang
Jessica
J
Latif
Shuaib
S
Garry
Mary G
MG
Garry
Daniel J
DJ
Longgood
Jamie
J
Frantz
Doug E
DE
Olson
Eric N
EN
Hsieh
Jenny
J
Schneider
Jay W
JW
D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D049409:Luciferases, Firefly / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D051381:Rats; D012038:Regeneration / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014335:Tropomyosin / Q000235:genetics; D000099251:Myocardin
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D006835:Hydrazones; D049409:Luciferases, Firefly; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014335:Tropomyosin; D000099251:Myocardin; C484469:Nkx2-5 protein, mouse