Abstract
Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. Despite extensive studies, knowledge of the molecular mechanisms underlying the early events associated with satellite cell activation and myogenic commitment in muscle regeneration remains still incomplete. Cripto is a novel regulator of postnatal skeletal muscle regeneration and a promising target for future therapy. Indeed, Cripto is expressed both in myogenic and inflammatory cells in skeletal muscle after acute injury and it is required in the satellite cell compartment to achieve effective muscle regeneration. A critical requirement to further explore the in vivo cellular contribution of Cripto in regulating skeletal muscle regeneration is the possibility to overexpress Cripto in its endogenous configuration and in a cell and time-specific manner. Here we report the generation and the functional characterization of a novel mouse model for conditional expression of Cripto, i.e., the Tg:DsRedloxP/loxPCripto-eGFP mice. Moreover, by using a satellite cell specific Cre-driver line we investigated the biological effect of Cripto overexpression in vivo, and provided evidence that overexpression of Cripto in the adult satellite cell compartment promotes myogenic commitment and differentiation, and enhances early regeneration in a mouse model of acute injury.
Highlights
The responses of skeletal muscle tissue following acute or chronic damages are highly complex and coordinated processes, involving many different cell populations that interact each other to promote muscle regeneration, inflammation and angiogenesis, until full regeneration of the tissue and its functional recovery
We have focused our attention on the developmental gene Cripto, which is a key regulator of vertebrate embryogenesis
By crossing transgenic line (Tg):DsRedloxP/loxPCripto-eGFP mice with a Tg:Pax7CreERT2 mouse line, we have investigated the effect of satellite cell- Cripto overexpression on skeletal muscle regeneration and overcome the limitation of the viralmediated approach (Guardiola et al, 2012)
Summary
The responses of skeletal muscle tissue following acute or chronic damages are highly complex and coordinated processes, involving many different cell populations that interact each other to promote muscle regeneration, inflammation and angiogenesis, until full regeneration of the tissue and its functional recovery. The satellite cells are activated and proliferate as myogenic progenitors that migrate to the damaged site, differentiate and fuse each other to form new myofibers (Hawke and Garry, 2001; Chargé and Rudnicki, 2004). This sequential process is correlated with the finely regulated expression of the Myogenic Regulatory Factors (MRFs). We report the generation and characterization of novel transgenic mice for conditional expression of Cripto in its endogenous configuration, which allowed us to study the biological effect of satellite cell-specific Cripto overexpression on muscle regeneration and myogenic cell fate determination
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