Skeletal Myoblasts Preserve Remote Matrix Architecture and Global Function When Implanted Early or Late After Coronary Ligation Into Infarcted or Remote Myocardium

Abstract

Background-The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes suggests that their beneficial effects on cardiac function after a myocardial infarction are mediated by paracrine effects. We evaluated the roles of these factors in the preservation of matrix architecture (in the infarct and remote regions) by varying the timing (postmyocardial infarction) and delivery site of the implanted cells. Methods and Results-Skeletal myoblasts (5ϫ10 6 ) or control media were injected into the infarct or noninfarcted myocardium at 5 or 30 days after coronary artery ligation in rats. Function was assessed by echocardiography before transplantation and 14 and 30 days thereafter and with a Millar catheter at 30 days after transplantation. Ventricular geometry, remote fibrillar collagen architecture, and changes in the matrix metalloproteinase-TIMP system were evaluated. Myoblast implantation in both sites and at both times preserved matrix architecture (length and width of collagen fibers) in the remote myocardium (in association with some decreases in remote myocardial matrix metalloprotease activity), improved global cardiac function, and attenuated the progressive increase in end diastolic volume (PϽ0.05 for all measures compared with medium controls). Cells delivered into the infarct region preserved scar thickness; cells delivered into the noninfarcted myocardium preserved wall thickness. Conclusions-Regardless of whether the cells were injected into the infarct or the noninfarcted myocardium early after an myocardial infarction or later, skeletal myoblasts improved cardiac function by preventing ventricular dilation and preserving matrix architecture in the remote region, likely mediated by paracrine effects. (Circulation. 2008;118[suppl 1]:S130-S137.)

Two‐photon microscopy of healthy, infarcted and stem‐cell treated regenerating heart

“…Further, injection of mesenchymal stem cells has been shown to improve cardiac function in rats by preserving remote matrix architecture and preventing ventricular dilation [20]. These two-photon results support the hypothesis that both limitation of collagen accumulation in the scar and prevention of necrosis of myocytes in the infarct region may be potential mechanisms of functional improvement by stem-cell regeneration.…”

Stem Cell Therapy for Chronic Myocardial Infarction

“…Thus, Li et al [37] investigated the outcome of fetal CM injected in a rat model of cryoinjury, showing that no transplanted cells were found 8 weeks after when immediately transplanted after injury, whereas CM injected 2 or 4 weeks later, when inflammation had disappeared, formed new tissue and positively affected cardiac function. Conversely, the group of Dr. Li found that injection of SkMyo, either in the infarcted or non-infarcted area of rats subjected to MI, induced a significant effect on cardiac contraction indistinctly of the time of injection (5 or 30 days post-MI) [16]. This group also found that the benefit was related to a greater prevention of ventricular dilatation and preservation of ECM architecture through influence in the MMP/TIMP system.…”

“…In spite of their lack of differentiation capacity [31] and their arrhythmyogenic potential [46], myoblast are able to act in a paracrine manner, secreting molecules capable of increasing the vascularization of the site as well as reorganizing the ECM [63]. In a rat model of chronic MI, Bonaros et al [7] showed that skeletal myoblasts (SkMyo) transplantation significantly affected ventricular function 1 month after injection which was later confirmed by Farahmand et al [16] who also found that the benefit was independent of the site of injection (into the infarction or in the remote zone). Moreover, Fukushima et al [20] reported that SkMyo transplantation either through the coronary veins or intramyocardially was beneficial for cardiac function and that this benefit was long-lasting (up to 3 months).…”

Myocardial infarction: The model of coronary artery ligation in Balb/C mice

“…After a period of 30 days, the animals were anesthetized and ventilated, as previously described, for echocardiographic examination, as described by Farahmand et al [18]. After tricotomy of the anterior thoracic region, the animals were placed in dorsal decubitus in a heated surgical bed for the appropriate positioning of the transducer in the left hemithorax of the animal.…”