Cardiac

Cellular therapies for primary cardiomyopathies have been proposed that aim to replace damaged cardiomyocytes and, over the last decade, cardiac cellular transplantation techniques have made significant gains. A variety of cell types have been evaluated as potential candidates for cardiac repair (Kessler and Byrne,

1999). Neonatal cardiomyocytes have been shown to survive and integrate when transplanted in healthy or injured myocardium (Leor et al., 1996; Scorsin et al., 1997, 1996). Immortalized cells derived from an atrial tumor also have been shown to survive and establish gap junctions in healthy, but not infarcted, porcine myocardium (Watanabe et al., 1998). Mesenchymal stem cells (MSCs) are an adult stem cell population that has received attention due to the suitability of MSCs for cell and ex vivo gene therapies. Initial reports indicated that human MSCs do not express MHC II markers, and express only low levels of MHC I (a characteristic that may allow the cells to escape surveillance by host immune cells) (Pittenger et al., 2000). Particular interest developed for the use of skeletal muscle myoblasts, as these cells have the potential for autologous transplantation (Ghostine et al., 2002; Menasche et al., 2001; Scorsin et al., 2000). Survival and differentiation of C2C12 myoblasts toward a slow-twitch muscle phenotype after arterial delivery into the murine heart has been demonstrated (Robinson et al., 1996). However, given the inherent differences between skeletal and cardiac myocytes, the ideal candidate for cellular cardiomyoplasty may be a less-committed progenitor cell that can be autologously isolated and undergo full cardiac differentiation. Muscle derived stem cells (MDSCs) have been transplanted into the murine myocardium and shown to integrate in SCID (Severe Combined Immunodeficiency) mice (Sakai et al., 2002) and to form gap junctions similar to true cardiomyocytes (Oshima et al., 2005). The functional impact of using bone-marrow cells for cellular cardiomyoplasty was demonstrated when Tomita et al. (1999) reported that adherent cells isolated from rat bone-marrow and treated with 5-azacytidine could improve heart function in a cryo-injury model of cardiomyopathy.

Given that noninvasive monitoring techniques will be essential for the clinical evaluation of stem cell transplants, many groups have explored the use of SPIO-labeled cells prior to transplantation into the beating myocardium. These efforts have included the use of hESC (Tallheden et al., 2006; Arai et al., 2006), MSCs, myoblasts, bone marrow (Walczak et al., 2005; 2006, 2006), macrophages (Leor et al., 2006), smooth muscle (Riviere et al., 2005), and EPCs (Weber et al., 2004b). An advantage of cardiovascular MRI is that both standard Tr and T2-weighted MR imaging sequences that are sensitive to SPIO-labeled cells can be simultaneously coupled with other diagnostic MR-imaging sequences used to determine viability, global, and regional cardiac function. It has been a long hope and the basis of cell therapies that transplanted cells would be able to "mend a broken heart" replacing fibrotic scar tissue with functional cardiomyocytes which are electrically connected to the rest of the heart and is the basis of many ongoing clinical trials (Chang et al., 2006; Laflamme and Murry, 2005). To this end both small and large animal preclinical models have been developed to track cell transplantation following an experimentally induced myocardial infarction. The challenge with small animals is the extremely high heart rate and small tissue mass that require optimized MR pulse sequences and hardware. Using a MR gradient recalled imaging sequence, gated to the ECG, cardiac images were acquired post-transplantation of SPIO-labeled myoblast along the entire long axis of the beating heart, with an in-plane resolution of 195 x 195 ^m2. Hypo-intense regions were clearly distinguishable in the left anterior wall of the animals receiving labeled transplants (Figure 6.6). The hypo-intense areas were present at all time points, although they did appear to become smaller and oriented with the curvature of the myocardial wall over time. Importantly, animals receiving unlabeled myoblasts did not exhibit discreet regions of intramyocardial hypo-intensity on T1 -weighted images. Histological analyses (Prussian Blue staining) demonstrated that the regions of intramyocardial MR signal loss correspond to the location of the engrafted myoblasts that had differentiated into myotubes (Figure 6.6). The rational for moving toward large animal studies is the ability to use image-guided catheter devices, similar to those used in clinical trials, providing endocardial cell delivery to targeted regions within the heart. This demand for interventional cardiovascular MR has pushed the development of low-field MRI devices (1.5 T) which are capable of simultaneous measurement of areas at risk (delayed contrast enhancement), 3D imaging, guidance of catheter delivery in real time and the imaging of SPIO-labeled cells once delivered to the heart (Dick et al., 2003; Saeed et al., 2005). The number and the region in which the cells are deposited (i.e., in the peri-infarct, infracted region, healthy myocardium) are extremely important to the overall success of the transplant.

Figure 6.6. Short (top-left) and long (top-right) axis MRIs of myoblast transplant in viable myocardium 24 h post-injection. Expression of skeletal fast-myosin (red) by the engrafted myoblasts (bottom-left). Prussian blue stain of engrafted myoblasts (bottom-right). Modified from Cahill et al. (2004b).

Figure 6.6. Short (top-left) and long (top-right) axis MRIs of myoblast transplant in viable myocardium 24 h post-injection. Expression of skeletal fast-myosin (red) by the engrafted myoblasts (bottom-left). Prussian blue stain of engrafted myoblasts (bottom-right). Modified from Cahill et al. (2004b).

Kraitchman et al. have demonstrated this dependence on location of cell delivery in a canine model of myocardial infarct. SPIO-labeled cells that were delivered to the peri-infarct and healthy myocardium were observed to have migrated to the infracted area. It is no doubt that with the numerous ongoing clinical trials using stem cells for heart failure the use of SPIO-labeled cells will play an expanding role in therapeutic monitoring and cell tracking.

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