Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium

Abstract

Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with diverse cytoprotective effects, and reported to have an important role in angiogenesis recently. Here we investigated whether HO-1 transduced by mesenchymal stem cells (MSCs) can induce angiogenic effects in infarcted myocardium. HO-1 was transfected into cultured MSCs using an adenoviral vector. 1 × 106 Ad-HO-1-transfected MSCs (HO-1-MSCs) or Ad-Null-transfected MSCs (Null-MSCs) or PBS was respectively injected into rat hearts intramyocardially at 1 h post-myocardial infarction. The results showed that HO-1-MSCs were able to induce stable expression of HO-1 in vitro and in vivo. The capillary density and expression of angiogenic growth factors, VEGF and FGF2 were significantly enhanced in HO-1-MSCs-treated hearts compared with Null-MSCs-treated and PBS-treated hearts. However, the angiogenic effects of HO-1 were abolished by treating the animals with HO inhibitor, zinc protoporphyrin. The myocardial apoptosis was marked reduced with significantly reduced fibrotic area in HO-1-MSCs-treated hearts; Furthermore, the cardiac function and remodeling were also significantly improved in HO-1-MSCs-treated hearts. Our current findings support the premise that HO-1 transduced by MSCs can induce angiogenic effects and improve heart function after acute myocardial infarction.

Transplantation of Adipose Tissue-Derived Stem Cells Overexpressing Heme Oxygenase-1 Improves Functions and Remodeling of Infarcted Myocardium in Rabbits

“…Therefore, overcoming the poor survival rate of implanted cells is clearly needed to improve stem cell therapy. In line with this, heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme, is now considered to function as a cytoprotective agent due to its multiple catalytic byproducts (Shibahara 2003); in fact, HO-1 has been shown to protect against apoptosis after oxidative stress injury in multiple cell types (Takahashi et al 1999;Abdel-Aziz et al 2003;Zeng et al 2010).…”

Advances in Mesenchymal Stem Cell Research in Sepsis

“…Future studies will also need to consider and compare the timeframe of administration of MSCs as well as the co-administration of adjunctive therapies such as fluid resuscitation, broad-spectrum antibiotics, low-dose glucocorticoids, or intensive insulin therapy employed in human sepsis. While numerous studies have examined ex vivo modifications of MSCs through preconditioning and genetic modifications in the treatment of myocardial infarction [47,[123][124][125][126][127][128][129][130], these approaches have not yet been exploited in animal models of sepsis and represent an exciting possibility for future research.…”

Preconditioning Approach in Stem Cell Therapy for the Treatment of Infarcted Heart

“…Besides survival signaling molecules, stem cells have also been modified genetically to express growth factors. Noticeable among these growth factors are Insulin-like growth factor (IGF-1), 116 hepatocyte growth factor (HGF), 190 stromal cell-derived factor-1a (SDF-1a), 191 VEGF,[192][193][194]195 sonic hedgehog, 197 FGF2,198 heme oxygenase, 199,200 and HIF-1a. 159 In our latest endeavor to exploit genetic modification of stem cells for preconditioning, we genetically modified syngenic rat skeletal myoblasts with a quartet of plasmids encoding for growth factors SDF-1a, HGF-1, VEGF, and IGF-1.…”