Central role for disabled-2 in mesenchymal stem cardiac protein expression and functional consequences after engraftment in acute myocardial infarction.
Adult mesenchymal stem cells (MSCs) have been shown to spontaneously express cardiac proteins (CP) in vitro and to improve cardiac function after transplantation into experimentally induced acute myocardial infarction (AMI). However, if these effects are the result of MSC cardiac differentiation or a mere cooperative cellular interaction is a matter of active debate. Additionally, the molecular mechanisms involved in CP expression by adult stem cells in vitro and its possible benefit for cardiac regeneration and improved function remain unclear. Here we show that although MSCs effectively engraft in AMI tissue, this engraftment leads to downregulation of CP expression in the implanted MSCs. We also found that pretransplantation cardiac specification of MSCs by exposure of the cells to transforming growth factor beta 1 (TGF-β1) led to sustained MSC CP expression without altering engraftment efficiency. This increase in CP expression was associated with greater improvement in cardiac function 1 and 4 weeks after AMI with TGF-β1-pretreated MSCs. We discovered that the TGF-β1-enhanced cardiac potential of MSCs was mediated by downregulation of disabled-2 (Dab2) expression, suggesting an inverse correlation between Dab2 levels and CP expression/cardiac functional improvement after MSC engraftment. Our investigations further demonstrate that loss of Dab2 expression was sufficient to induce MSC CP expression and improve cardiac function after MSC engraftment after AMI. In summary, we define a novel role for the TGF-β1 receptor adaptor protein Dab2 as a regulator of CP expression in MSCs and its potential as a molecular target for the enhancement of stem cell cardiac specification for transplantation therapies.
Mayorga
Maritza E
ME
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
Dong
Feng
F
Sundararaman
Srividy
S
Huang
Yanming
Y
Jiang
Yong
Y
Howe
Philip H
PH
Penn
Marc S
MS
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D026161:MADS Domain Proteins / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D034622:RNA Interference; D051381:Rats; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019210:Troponin I / Q000378:metabolism; D015854:Up-Regulation; D024723:Ventricular Myosins / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; C501404:Dab2 protein, rat; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins; D016212:Transforming Growth Factor beta; D019210:Troponin I; D003094:Collagen; D024723:Ventricular Myosins