RESUMO
Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells.
Assuntos
Desenvolvimento Muscular , Receptor Notch1/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Animais , Proteínas de Ligação ao Cálcio , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Receptor Notch1/genética , Células-Tronco/metabolismoRESUMO
A study was made of 19 male subjects, mean age 54.7, S.D. 7.5 years, exposed to risk of aluminium dust inhalation for 16, S.D. 9.7 years, awarded compensation by the local provincial branch of INAIL (National Institute for Insurance against Occupational Accidents) in the period 1975-1988, as prescribed by item 48 of Presidential Decree 482/1975. The workers were divided into two groups on the basis of radiological signs of lung fibrosis (3 1/1 cases and 7 1/0 cases according to the ILO classification) or of COPD (Chronic Obstructive Pulmonary Disease) (9 cases). Careful examination of the work histories confirmed the previous observations of aluminium pneumoconiosis with moderate functional alterations in alumina production, potroom and casting workers.
