Fibrotic remodeling and tissue regeneration mechanisms define the therapeutic potential of human muscular progenitors.

Fibrosis is an intrinsic biological reaction toward the challenges of tissue injury that is implicated in the wound-healing process. Although it is useful to efficiently mitigate the damage, progression of fibrosis is responsible for the morbidity and mortality occurring in a variety of diseases. Because of lacking effective treatments, there is an emerging need for exploring antifibrotic strategies. Cell therapy based on stem/progenitor cells is regarded as a promising approach for treating fibrotic diseases. Appropriate selection of cellular sources is required for beneficial results. Muscle precursor cells (MPCs) are specialized progenitors harvested from skeletal muscle for conducting muscle regeneration. Whether they are also effective in regulating fibrosis has seldom been explored and merits further investigation. MPCs were successfully harvested from all human samples regardless of demographic backgrounds. The extracellular matrices remodeling was enhanced through the paracrine effects mediated by MPCs. The suppression effects on fibrosis were confirmed in vivo when MPCs were transplanted into the diseased animals with oral submucous fibrosis. The data shown here revealed the potential of MPCs to be employed to simultaneously regulate both processes of fibrosis and tissue regeneration, supporting them as the promising cell candidates for development of the cell therapy for antifibrosis and tissue regeneration.

Mevalonate Pathway Enzyme HMGCS1 Contributes to Gastric Cancer Progression.

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.