Antonio Musarò

The physiopathologic role of tissue niche in muscle regeneration

The prolongation of skeletal muscle strength in neuromuscular disease has been the objective of numerous studies employing a variety of approaches. Stem cell therapy represents a promising tool to cure genetic diseases. However, this approach is not definitive yet and several hurdles limit the immediate translation of this strategy into clinic.

One of the crucial parameters of tissue regeneration is the microenvironment in which the stem cell populations should operate. Stem cell microenvironment, or niche, provides essential cues that regulates stem cell proliferation and that directs cell fate decisions and survival. It is therefore plausible that loss of control over these cell fate decisions might lead to a pathological transdifferentiation and contribute to the exacerbation of a pathologic condition, such as muscular dystrophy.

Among critical parameters, the activation and persistence of inflammatory and fibrotic pathways may render the dystrophic muscle incapable to sustain and complete an efficient muscle regeneration, leading to a progressive loss of muscle tissue due to chronic degeneration of muscle and to the exhaustion of satellite cells that replace damaged fibers. Indeed, the progressive loss of tissue function and integrity observed in dystrophic muscles are the eventual consequences of a history of continuous rounds of degeneration and regeneration.

Specific factors are required to trigger stem cells toward a specific lineage, to improve their survival, and to render them effective in contributing to tissue repair. Studies on stem cell niche leaded to the identification of critical players and physiological conditions that improve tissue regeneration and repair.

Preliminary evidences demonstrated that the local form of Insulin-like Growth Factor–1 (mIGF-1) sustains muscle hypertrophy and regeneration in senescent skeletal muscle, enhances the recruitment of circulating stem cells in injured muscle and counteracts muscle wasting in mdx dystrophic mice, reducing the inflammatory response and improving muscle mass and strength and elevating pathways associated with muscle survival and regeneration. Among the factors modulated by mIGF-1, we observed a specific down-regulation of the inflammatory cytokines IL-6, which has been associated with the switch from acute to a chronic inflammatory response that therefore can exacerbate the dystrophic phenotype. We will discuss the role of mIGF-1 and IL-6 in the modulation of muscle regeneration under physiological and pathologic conditions.

 

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