A potent source of stem cells to
A potent source of stem bcr-abl inhibitors to improve outcome after AMI is the stromal vascular fraction of adipose tissue (SVF), which contains adipose derived stem cells (ASC). ASCs have properties similar to bone marrow mesenchymal stem cells as has been shown in vitro and in vivo (Zhu et al., 2008; Zuk et al., 2002), and have the capacity to differentiate towards cardiomyocytes (Gaustad et al., 2004; Rangappa et al., 2003; Zuk et al., 2002). In addition, cultured ASCs have already been shown to improve left ventricular function in a porcine AMI model (Valina et al., 2007). Currently a clinical trial (APOLLO) investigates the safety and feasibility of ASCs transplantation in humans (Meliga et al., 2007). However, although these studies are very promising, further optimization is needed. Compared to bone marrow, adipose tissue provides up to 100 times more stem cells per gram, which facilitates the use of uncultured stem cells, or the whole SVF population, as such for transplantation purposes after AMI (Oedayrajsingh-Varma et al., 2006; Zhu et al., 2008). This is advantageous for clinical practice, since culturing is time consuming and expensive (Oedayrajsingh-Varma et al., 2006), and may affect the functional characteristics of stem cells (Rombouts and Ploemacher, 2003), which theoretically may lead to complications during transplantation (Zhu et al., 2008). In this study we therefore compared injection of fresh SVF cells with cultured ASCs in a rat model of AMI.
In addition, we investigated the optimal time point for stem cell delivery, since the time after reperfusion dictates the cellular and humoral environment after AMI, which in turn is an important determinant of the efficacy of stem cell therapy (Azarnoush et al., 2005; Wang and Sjoquist, 2006). During the acute phase of infarction massive myocardial necrosis and leukocyte infiltration may namely harm survival of implanted cells (Lu et al., 2004). Furthermore, it is known that homing and differentiation of stem cells after AMI depends on adhesion factors formed at the site of injury (Azarnoush, 2005; Malek et al., 2006; van Dijk et al., 2008a). It is therefore important to apply stem cell therapy at a time point after infarction when the environment is most favorable for stem cell survival, adhesion and cardiomyocyte formation. However, to the best of our knowledge, this ideal time frame has not yet been determined. In most animal studies, investigators namely apply stem cells during the same operational procedure as the infarct induction. Whereas recent studies have shown that later time points may be more favorable for the survival of the stem cells (Bermejo et al., 2006; Lu et al., 2004; Wang and Sjoquist, 2006). We therefore hypothesized that transplantation after the acute inflammation period (7days after AMI) would be favorable over early injection (within 1day after AMI). Taken together, in this study we wanted to compare the effects of intravenous injection of fresh SVF cells and cultured ASCs at different time points on infarct size and outcome in AMI.
Materials and methods
Discussion In this study we investigated in an immunocompetent rat model of AMI with reperfusion, whether intravenous injection of uncultured SVF or cultured ASCs 7days after AMI, improved AMI outcome, and finally compared this with injection of SVF cells 1day after AMI. It was found that intravenous delivery of stem cells (both SVF and cultured ASCs) 7days after AMI significantly reduced infarct size, and improved cardiac function. We further found that stem cells could be detected in the infarcted area and had differentiated towards cardiomyocytes, although the amount of retrieved cells was limited. Stem cell therapy did not significantly improve vascular density, however we found a trend towards an increased number of arterioles and total vessels in the infarcted area, but not in the border zone, after treatment with SVF cells and cultured ASCs. The number of macrophages in the infarcted area was not significantly affected by cell therapy. No adverse effects were found after injection of SVF, whereas a detrimental effect on respiratory function was found in three animals in which cultured ASCs were used. Finally, it was found that in contrast to injection 7days after AMI, injection of SVF cells 1day after AMI, only resulted in a small non-significant infarct reduction.