Functional effects of myoblast implantation into histoincompatible mice with or without immunosuppression.

Abstract

1. The goals of this study were to evaluate the immunogenicity of myogenic cells (MCs) (1) immediately after implantation into regenerating muscles, and (2) following their maturation under initial immunosuppression. Implanted mouse soleus muscles were evaluated by isometric tension recordings in vitro followed by histological investigations on frozen sections. 2. Implantation of non‐histocompatible myoblasts into cryodamaged soleus muscles of CBA/J mice induced immune rejection which caused large and permanent deficits in muscle force: 4‐42 weeks postimplantation maximal tetanic tension was 50‐60% that of intact or regenerated cryodamaged control muscles without tendency for recovery or histological signs of muscle regeneration. Specific tension (force per unit muscle weight) was also significantly reduced. 3. On frozen sections, only 62 +/‐ 12% of the total area was desmin‐positive, that is, occupied by muscle fibres, versus 90 +/‐ 4% in regenerated and 92 +/‐ 3% in intact muscles. Also, the total number of muscle fibre profiles was significantly reduced. 4. Under immune suppression with cyclosporin A (CsA), large muscles developed within 4 weeks. Following CsA withdrawal, muscle weight and force, in addition to desmin‐positive areas on cross‐sections, gradually declined over several months despite continual regeneration, indicating retarded immune rejection. 5. Initial application of CsA for 8 weeks after implantation, instead of 4 weeks, did not result in better survival of the implants, nor did a higher initial dose of CsA (100 instead of 50 mg kg‐1 day‐1). Prolonged continuous application of a reduced dose (25 mg kg‐1 day‐1) did not prevent muscle wasting but caused an additional delay. 6. It is concluded that histoincompatible myoblasts are highly immunogenic and that immune rejection causes large and permanent muscle deficits indicating elimination of host muscle tissue. Initial transient immunosuppression protects the incompatible cells, but after withdrawal, prolonged immune rejection and retarded muscle wasting occur.

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

“…After 6.5 weeks, each animal group was split in 2 subgroups, one treated with CsA (Sandimmume Neoral, Novartis) in saccharine-flavored drinking water and the other receiving just saccharine-flavored water. In view of the reported dose of CsA tolerated by mice (79), CsA concentration in drinking water was calculated to deliver a dose of 8 mg/kg/d during the 2 first days. Then it was increased to deliver 16 mg/kg/d for 2 more days and finally maintained at 24 mg/kg/d until the end of treatment.…”

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…This may be erroneously taken as a proof that tolerance is easily obtainable in myoblast transplantation. However, tolerance was not observed in other mouse strains in the same conditions [21,183]. Importantly, acute rejection of hybrid myofibers always occur in nonhuman primates following transient immunosuppression, regardless if it lasts for months and is decreased slowly [121,180,181].…”

“…So far, this property was unequivocally confirmed only in transplantation of myoblasts. Myoblast transplantation was the only type of myogenic cell transplantation in mice that was able to completely or almost completely regenerate muscles destroyed by different acute treatments, recovering muscle mass and strength [19][20][21][22]. Nevertheless, these acute experimental conditions are different from a chronic degenerative myopathy.…”

“…Another possibility (more accessible to laboratories that do not have access to irradiation equipment) is cryodamage. In this case, freezing the recipient muscles combines myofiber necrosis with killing the recipient's satellite cells, and it was used in mice as a pretreatment to increase the engraftment of the implanted myogenic cells [21,22,36,38].…”

“…Given that it is an antiproliferative drug, it was suggested that cyclophosphamide kills the transplanted cells as soon as they proliferate [182]. Cyclosporine A was effective for the engraftment of myoblasts in some mouse experiments [21,175,183,184]. However, cyclosporine inhibited myoblast fusion in vitro at therapeutic doses [185], blocked myoblast differentiation [186], and induced apoptosis in these cells [186], properties that could be detrimental for myogenic cell transplantation.…”