Somatic cell transplantation

Transplantation of somatic cells to supply the function of a deficient organ has been successfully performed for decades for bone marrow, and more recently, only with inconsistent results, for skeletal muscles (Duchenne dystrophy), liver (as a bridge to transplantation), pancreas (islets of Langerhans) or brain.2 It has been shown that minced fetal brain tissue can be grafted within the brain of Parkinsonian patients, increasing dopamine secretion and decreasing symptoms. Like brain cells, adult ventricular myocytes are terminally differentiated, with no possibility of cell division from neonatal age; thus, following injury (infarction), repair consists of scar formation, hypertrophy of surviving myocytes, and hyperplasia of non-muscle cells such as fibroblasts (remodelling). These phenomena become deleterious over time and do not address the initial problem, the loss of contractile cells. Thus, as with Parkinson's disease, cultured fetal cells have been first used as intramyocardial grafts.

Intramyocardial grafting

Which are the optimal cells?

The aim is to obtain the highest number of myogenic cells for transplantation, their culture being an essential step. Thus, these cells must possess a high potential for division during culture, and ideally have a potential for further multiplication after grafting. Immortalised cultured myogenic cell lines have been used experimentally but there is a potential for cancer which limits a potential human use. Fetal cardiomyocytes—which can divide normally—have been successfully grafted into the myocardium, but their use raises immunological, ethical, and availability problems. Thus, it appears that cultured autologous myogenic cells are an optimal support, as they obviate the need for immunosuppressive treatment. Skeletal myoblasts (also called satellite cells and functionally indistinguishable from embryonic myoblasts) are stem cells located at the basal lamina of the adult skeletal muscle, are highly resistant to ischaemia, and may multiply after injury (each myoblast can supply about 12 mitoses); this explains why iatrogenic rhabdomyolysis can be followed by a restitution ad integrum after removal of the causal drug. From a clinical perspective, the use of cultured autologous myoblasts requires a strict protection against bacterial, viral or prion contamination, and a high efficacy of cell culture. We have now developed techniques which enable us to obtain hundreds of thousands of myoblasts from a single human muscular biopsy weighing a few grams (authors' unpublished data). Bone marrow stem cells are also able to differentiate into myogenic cells,14 but their clinical use remains hypothetical. In the future, adjunctive treatments could include ex vivo genetic engineering targeted at preventing apoptosis or increasing angiogenesis; moreover, cells might be delivered using intracardiac catheters instead of thoracotomy.

Unresolved questions

The mechanisms of these beneficial effects remain controversial. It is not certain whether improvement in left ventricular performance is mediated by an increased systolic function caused by synchronous contraction of the graft. An indirect systolic effect—mediated by angiogenic or growth factors secreted by transplanted cells—is suggested by the improvement of global function of locally injected cells.8 A passive girdling effect, simply limiting progressive cavity dilatation and decreasing pump function, is likely. Increased myocardial thickness caused by local injection may decrease wall stress, thus improving function and reducing infarct expansion. Recent experimental studies have suggested a direct systolic effect (increased systolic thickening) of myogenic cell transplantation in the infarcted area.11 It is noteworthy, however, that a significant improvement in function requires transplantation of contractile cells, as intramyocardially grafted fibroblasts are far less effective.

From bench to bedside

Thus, cellular transplantation into a damaged myocardium results in an obvious improvement in left ventricular performance and remodelling. Experiments have shown a similar efficacy of fetal and satellite cells, using either allogenic or preferably autologous grafts which do not raise any immunological, ethical, tumorigenesis, or donor availability problems; this opens the way to human trials in the near future. The first clinical applications should ideally be the postinfarction patient with a low ejection fraction and an indication for coronary artery bypass surgery. After skeletal muscular biopsy, cultured autologous myoblasts could be directly administered by multiple injections within and around the infarcted area during surgery. The first step will be to check the feasibility of the whole procedure (from biopsy to reinjections after large scale cell expansion) and its safety (absence of induced arrhythmias); its efficacy, which is suggested by a wealth of experimental data in different species using multiple evaluation techniques, will then have to be clinically proven.