Restoration of functional motor units in a rat model of sphincter injury by muscle precursor cell autografts.

Abstract

Urinary incontinence is a debilitating condition that affects primarily elderly individuals. One major mechanism results from chronic denervation of the striated urethral sphincter with associated fibrosis. The authors investigated the fate of muscle precursor cells (MPC) injected into a model of striated urethral sphincter injury that reproduces the histopathologic changes of sphincter insufficiency. The striated urethral sphincter of older male rats was damaged by electrocoagulation. MPC were isolated from limb myofiber explants, infected with an adenovirus carrying the transgene encoding beta-galactosidase, and injected into the sphincter of the same animal 37 days after injury. Animals were killed 5 and 30 days after injection for assessment of sphincter function and the formation of motor units. Electrocoagulation resulted in an irreversible destruction of both sphincteric myofibers and nerve endings, with a functional incapacity of the damaged sphincter to sustain an increase in bladder pressure; atrophy and fibrosis developed after 1 month. Injection of MPC resulted in the formation of beta-galactosidase-expressing myotubes in the sphincter that persisted beyond 30 days. The regenerated myotubes carried acetylcholine receptors associated with a nerve ending and were thus considered to form anatomic motor units. Urodynamic studies confirmed the restoration of 41% of sphincter function 1 month after MPC injection. The authors showed that MPC isolated from limb muscles of an older animal can recapitulate a myogenic program when injected into an irreversibly injured sphincter. The maturation of MPC activates nerve regeneration and restores functional motor units.