Myocardial survival signaling in response to stem cell transplantation.
BACKGROUND
Experimental human stem cell transplantation to the heart has begun, but the mechanisms underlying benefits seen in preclinical models, both at the site of cell injection and at more distant regions, remain uncertain. We hypothesize that these benefits can be best understood first at the level of key intracellular signaling cascades in the host myocardium, which can be responsible for functional and structural preservation of the heart.


METHODS
Western blot and ELISA were used to assess key pathways that regulate cardiac myocyte survival and hypertrophy in both the infarct/borderzone and remote myocardium of C57/B6 mouse hearts subjected to coronary artery ligation, with subsequent injection of either vehicle or bone marrow-derived adult mesenchymal stem cells (MSC).


RESULTS
Improved left ventricular function with MSC transplantation was associated with a relative preservation of Akt phosphorylation (activation) and of phosphorylation of downstream mediators of cell survival and hypertrophy. There was no substantial difference in activation of mitogen-activated protein kinase p38, and activation of the antiapoptotic mitogen-activated protein kinase extracellular signal-regulated kinase was lower at 1 week after MSC treatment, but rose beyond controls by week 2. Similar changes were observed in both the infarct/borderzone and the remote myocardium.


CONCLUSIONS
Stem cell transplantation in the post-MI murine myocardium is associated with preservation of Akt signaling. Together with a possible later increase in extracellular signal-regulated kinase activation, this signaling change might be responsible for cardioprotection. Additional focused investigation might identify elements in transplantation regimens that optimize this mechanism of benefit, and that can increase the likelihood of human clinical success.
Li
Hongzhe
H
Division of Cardiothoracic Surgery, University of California, San Francisco, CA 94143, USA.
Malhotra
Deepak
D
Yeh
Che-chung
CC
Tu
Richard
R
Zhu
Bo-Qing
BQ
Birger
Noy
N
Wisneski
Andrew
A
Cha
John
J
Karliner
Joel S
JS
Mann
Michael J
MJ
D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology
D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases