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After intra-arterial delivery in the dystrophic dog, allogeneic muscle-derived stem cells, termed MuStem cells, contribute to long-term stabilization of the clinical status and preservation of the muscle regenerative process. However, it remains unknown whether the human counterpart could be identified, considering recent demonstrations of divergent features between species for several somatic stem cells. Here, we report that MuStem cells reside in human skeletal muscle and display a long-term ability to proliferate, allowing generation of a clinically relevant amount of cells. Cultured human MuStem (hMuStem) cells do not express hematopoietic, endothelial, or myo-endothelial cell markers and reproducibly correspond to a population of early myogenic-committed progenitors with a perivascular/mesenchymal phenotypic signature, revealing a blood vessel wall origin. Importantly, they exhibit both myogenesis in vitroand skeletal muscle regeneration after intramuscular delivery into immunodeficient host mice. Together, our findings provide new insights supporting the notion that hMuStem cells could represent an interesting therapeutic candidate for dystrophic patients.

Duchenne muscular dystrophy (DMD) is a genetic progressive muscle disease resulting from the lack of dystrophin and without effective treatment. Adult stem cell populations have given new impetus to cell-based therapy of neuromuscular diseases. One of them, muscle-derived stem cells, isolated based on delayed adhesion properties, contributes to injured muscle repair. However, these data were collected in dystrophic mice that exhibit a relatively mild tissue phenotype and clinical features of DMD patients. Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog's clinical status. These results demonstrate that MuStem cells could provide an attractive therapeutic avenue for DMD patients.

The article presents a preclinical trial of cell therapy on dogs with duchenne muscular dystrophy (DMD). The trial isolated a muscle stem cell (MuStem) which have important requirements for therapeutic use including the ability to fuse with muscle fibers, high amplification capacity, and dramatic clinical improvement of the animal. Result shows that it offers a solution for the therapeutical trial on children with muscular dystrophy.

Transforming growth factor-β1 (TGF-β1) has been shown to down-regulate NO synthesis in a variety of normal cells. In the present study, we investigated the influence of TGF-β1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon carcinoma cells intraperitoneally injected in syngeneic BDIX rats, intratumoral concentration of TGF-β1 increases while NO concentration stays very low. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-β1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-β1-secreting cells. Using PROb cells transfected with an expression vector coding for TGF-β1 antisense mRNA, we demonstrate in vitrothat there is an inverse correlation between the amount of TGF-β1 secreted and the ability of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-β type II receptor neutralizing antibody, and as exogenous TGF-β1 is without any effect on NO secretion by PROb cells, TGF-β1 apparently down-regulates NO synthesis in PROb cells by an intracellular mechanism. These results suggest that endogenous TGF-β1 constitutes a potential target in a search for new antitumoral agents.

In order to elucidate the role of myofibroblasts in tumor development, we compared fibroblastic reactions and their implications in the immune response in progressive and regressive rat colorectal-tumor models. Immunohistochemical analyses revealed that T lymphocytes and monocytes/macrophages were found outside progressive tumors that were surrounded by a large sheath of myofibroblasts. In vitro experiments using fibroblast- vs. myofibroblast-containing collagen gels showed that the mechanical properties of these tumor-activated myofibroblasts prevent penetration of T lymphocytes and macrophages within tumor nodules. These results indicate that tumor-activated myofibroblasts may prevent physical contact between cancer-cells and immune cells, an essential phenomenon for effective destruction of cancer cells. Successful immunotherapy against cancer should therefore include complementary treatments against these tumor-associated fibroblasts. Int. J. Cancer 81:629–636, 1999. © 1999 Wiley-Liss, Inc.

The prominent desmoplastic or stromal reaction seen in many invasive carcinomas suggests that stromal cells play a role in cancer pathogenesis. Investigations based on cell typing, using antibodies to cytoskeletal constituents, have revealed that most tumors contain various types of fibroblasts. Stromal cells with myofibroblastic differentiation features are the predominant cell type at the periphery of epithelial tumors. These tumoractivated fibroblasts play a major role in tumor development and spread, affecting the proliferation, differentiation, invasion or regression of cancer cells. This review considers the events inducing the different fibroblastic responses and the role of tumor-activated fibroblasts in both tumor development and anti-cancer treatments.