Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function.
OBJECTIVE
Myocardial infarction (MI) is associated with irreversible loss of viable cardiomyocytes. Cell therapy is a potential option to replace the lost cardiomyocytes and restore cardiac function. However, cell therapy is faced with a number of challenges, including survival of the transplanted cells in the infarct region, which is characterized by abundant levels of oxidants and lack of a pro-survival support mechanism. The goal of the present study was to evaluate the effect of supplemental oxygenation on cell engraftment and functional recovery in a rat model.


RESULTS
MI was induced in rats by a 60-min occlusion of the coronary artery, followed by restoration of flow. Mesenchymal stem cells (MSCs), isolated from adult rat bone marrow, were transplanted in the MI region. Rats with transplanted MSCs were exposed to hyperbaric oxygen (HBO: 100% O(2), 2 atmospheres absolute) for 90 min, 5 days/week for 4 weeks. The experimental groups were: MI (control), Ox (MI + HBO), MSC (MI + MSC), and MSC + Ox (MI + MSC + HBO). HBO exposure (oxygenation) was started 3 days after induction of MI. MSCs were transplanted 1 week after induction of MI. Echocardiography showed a significant recovery of cardiac function in the MSC + Ox group, when compared with the MI or MSC group. Oxygenation increased the engraftment of MSCs and vascular density in the infarct region. Molecular analysis of infarct tissue showed a four-fold increase in NOS3 expression in the MSC + Ox group compared with the MI group.


CONCLUSIONS
The results showed that post-MI exposure of rats to daily cycles of hyperoxygenation (oxygen cycling) improved stem cell engraftment, cardiac function, and increased NOS3 expression.
Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, 43210, USA.
Mahmood
M
Khan
Sarath
S
Meduru
Rajan
R
Gogna
Esha
E
Madan
Lucas
L
Citro
Muthulakshmi L
ML
Kuppusamy
Muzzammil
M
Sayyid
Mahmoud
M
Mostafa
Robert L
RL
Hamlin
Periannan
P
Kuppusamy
D000818:Animals; D001483:Base Sequence; D003131:Combined Modality Therapy; D018031:Connexin 43 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D006931:Hyperbaric Oxygenation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D018031:Connexin 43; D017931:DNA Primers; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat