Skeletal myoblasts

Skeletal myoblasts are adult, tissue-specific stem cells [73] located between the basal lamina and the sarcolemma on the periphery of the mature skeletal-muscle fiber [74]. Also known as muscle satellite cells, these small, mononuclear cells are activated by biochemical signals to divide and differentiate into fusion-competent cells after muscle injury. 

The use of skeletal myoblasts for cardiac repair originated from earlier attempts where fetal cardio-myocytes were used. When injected into the border... 

Skeletal myoblasts are viewed as an attractive alternative by some [76]. The first therapeutic trials used skeletal myoblasts obtained under sterile conditions and local anesthesia from 0.5- to 5.0-g muscle biopsy specimens. Individual cells were isolated by digestion with trypsin and collagenase, washed to remove red blood cells and debris, plated, and cultured to obtain the numbers necessary for therapeutic use. 

Skeletal myoblasts can survive prolonged periods of hypoxia [77]. Like fetal cardiomyocytes, skeletal myoblasts survive and may engraft (although this is controversial) when injected into the border zone of an AMI. 

Transcoronary venous injection is performed with a catheter system threaded percutaneously into the coronary sinus. Initial studies in swine have confirmed the feasibility and safety of this approach [121]. This delivery method has also been used to deliver skeletal myoblasts to scarred myocardium in cardiomyopathy patients [120]. With intravascular ultrasound guidance, this approach allows the operator to extend a catheter and needle away from the pericardial space and coronary artery into the adjacent myocardium. To date, human feasibility studies have had a good safety profile. This technique is limited, however, by coronary venous tortuosity, lack of site specific targeting, and its own technically challenging nature. Unlike the transendocardial approach, in which cells are... 

Clinical research with bone marrow-derived stem cells has focused on the period immediately after an AMI and on the chronic phase of ischemic heart disease. In these clinical scenarios, therapy has been targeted to viable myocardium with or without systolic heart failure. On the other hand, skeletal myoblast therapy has been used to treat ischemic heart failure involving nonviable myocardium or scar... 

Most of the clinical experience gained with stem cells has involved therapy for AMI, particularly intracoronary infusion of bone marrow cells since skeletal myoblasts are too large for this purpose [133]. Table 7.2 summarizes the experience to date. In all of these trials, revascularization was performed promptly after the index myocardial infarction, and left ventricular systolic compromise was minor (in the BOOST trial, the baseline left ventricular ejection fraction [LVEF] was 50%). 

Clinical trials of skeletal myoblasts have focused on the treatment of patients with ischemic cardiomyopathy and systolic dysfunction. Overall, these trials have resulted in improved segmental contractility and global LVEF. The preferred delivery route has been surgical intramyocardial injection, and one feasibility trial of transendocardial injection has been reported in the literature so far. 

Tambara K, Sakakibara Y, Sakaguchi G, Lu F, Premaratne GU, Lin X, Nishimura K, Komeda M. Transplanted skeletal myoblasts can fully replace the infarcted myocardium when they survive in the host in large numbers. Circulation 2003 108 Suppl 1 11259-263. 

Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin N, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003 41 1078-1083. 

Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzezniczak J, Rozwadowska N, Kurpisz M. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury phase I clinical study with 12 months of follow-up. Am Heart J 2004 148 531-537. 

Siminiak T, Fiszer D, Jerzykowska O, Grygielska B, Rozwadowska N, Kalmucki P, Kurpisz M. Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment the POZNAN trial. Eur i/eart / 2005 26 1188-1195. 

Smits PC, van Geuns RJ, Poldermans D, Bountioukos M, Onderwater EE, Lee CH, Maat AP, Serruys PW. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure chnical experience with six-month follow-up. J Am Coll Cardiol 2003 42 2063-2069. 

For angiogenesis and vasculogenesis, the following cells can be proposed ECs, bone marrow-derived stem cells, and circulating blood-derived progenitor cells, For myogenesis, skeletal myoblasts, smooth muscle cells, or fetal and neonatal cardiomyocytes can be used, The relative contribution of various sources of precursor cells in postnatal muscles and the factors that may enhance stem cell participation in the formation of new skeletal and cardiac muscle in vivo have... 

Chachques JC, Cattadori B, Herreros J, et al. Treatment of heart failure with autologous skeletal myoblasts. Herz 2002 27 570-578. 

Taylor DA, Atkins BZ, Hungspreugs R et al. Regenerating functional myocardium improved performance after skeletal myoblast transplantation. Nat Med 1998 4 929-933. 

In the past 15 years, an extensive amount of preclinical data has been on the reparative potential of cell transplantation in acute and chronic myocardial injury. Since the first preclinical report of functional repair after the injection of autologous skeletal myoblasts into the injured heart in 1998 (7), a variety of cell types or combinations (Table I) have been proposed for transplantation during different stages of CVD (19). Preclinical data has been promising, and in at least one study, the amount of repair achieved with cell transplantation in HF is additive to current medical treatment (20). With the first cardiac clinical application in 2001 (8), the field rapidly moved from bench to bedside, and at present, we are gaining valuable information about the questions to ask and the early answers from both animal and human studies. To date, 19 clinical trials either in AMI (Table 2) or chronic HF have been published (21) (Table 3), including 13, where BM... 

Hutcheson et al. (82) Rabbit Cryoinjury Skeletal myoblasts vs. fibroblasts SKM superior to FB SKMB improve systolic and diastolic function FB only improves diastolic... 

Thompson et al. (30) Rabbit Cryoinjury Skeletal myoblasts vs. bone marrow mononuclear cells No difference between SKMB and mononuclear bone marrow stem cells regarding LV function... 

Horackova et al. (28) Guinea pig LAD ligation Skeletal myoblasts vs. cardiac fibroblasts vs. cardiomyocytes Myotube formation in SKMB-treated animals SKMB superior to CM and CFs regarding remodeling functional improvement in SKMB-treated animals no comparison regarding the LV function... 

Agbulut et al. (31) Rat LAD ligation Human skeletal myoblasts vs. human AC133 + Myotubes in SKMB-treated group no difference regarding the LV function... 

Ott et al. (29) Rat LAD ligation Autologous skeletal myoblasts vs. BM-MNC SKMB superior to isolated BM-MNC regarding LV function Combination of... 

Experimental studies comparing different cell types in cellular cardiomyoplasty. Skeletal myoblasts have a higher myogenic potential, whereas bone marrow-derived stem cells seem to be more capable of inducing angiogenesis. Several cell types lead to functional improvement. One study suggests synergistic effects of different cell types in combined treatment. 

Abbreviations BM-MNC. tone marrow mononuclear cell CF. cardiac fibroblast CM, cardiomyocyte FB. fibroblast LAD. left anterior descending artery LV, left ventricle SKMB, skeletal myoblast. 

Abbreviations BM-MNC, bone marrow mononuclear cell CABO, coronary artery bypass grafting CPC, circulating progenitor cells LV. left ventricle LVED. left ventricular end-diastolic diameter LVEDV, left ventricular end-diastolic volume LVEF, left ventricular ejection fraction NYHA, New York Heart Association SKMB, skeletal myoblast. 

Under these conditions, naturally myogenic cells, such as skeletal myoblasts, cardiocytes, or any progenitor cell driven down a muscle lineage appear the logical first choice. However, the ultimate proof of any cell superiority will require side-by-side comparisons of cells in similar disease state studies, which to date are limited or nonexistent. 

Other mechanistic approaches to cell therapy can also be envisioned, For example, a characteristic of compensated cardiac hypertrophy is the reduction of mechanical stress—a clear call for cells that are able to stabilize scar. Mesenchymal BM cells, fibroblasts, and skeletal myoblasts (all mesoderm-derived progenitors) improve diastolic function and reduce wall stress (30). The BN-MNC, peripheral blood endothelial progenitor cells (EPCs), and umbilical cord blood (UCB) cells... 

A serious deleterious outcome associated to date primarily with myoblasts (and with thawed BM in chemotherapy patients) (50) is the incidence of cardiac electrical instability for a presumed transient period after cell delivery. These early reports of electrical instability in patients after the receipt of autologous skeletal myoblasts have led to doubts about the safety of these cells as a treatment in the injured heart. Patients who received myoblasts in the earliest clinical studies (33,38) were extremely ill patients with an expected high potential for negative electrical events. In fact, many of the patients who were included in the early trials met the Multicenter Automatic Defibrillator Implantation Trial MADIT-II criteria, which were presented after those trials began, and suggested that all patients who met those criteria be treated with AlCDs. As a result, in more recent clinical studies, many investigators have only enrolled patients who receive AlCDs... 

Looking at the results of both preclinical and clinical studies, we recognize the potential of cardiac cell transplantation to alter outcomes. However, we have to admit that in most cases, we do not understand how different cell types improve LV function. Increases in microvascular density, diastolic and systolic function, and an attenuated remodeling, are all reported after the application of many different cell types, but the exact mechanisms are unclear. Only a few studies address the elec-trophysiologic fate of the injected cells (71,72). In these studies, skeletal myoblasts were found to be isolated from the surrounding myocardium, and they underwent severe... 

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