Evaluation of pro-regenerative and anti-inflammatory effects of isolecanoric acid in the muscle: Potential treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating degenerative disease of skeletal muscles caused by loss of dystrophin, a key protein that maintains muscle integrity, which leads to progressive muscle degeneration aggravated by chronic inflammation, muscle stem cells' (MuSCs) reduced regenerative capacity and replacement of muscle with fibroadipose tissue. Previous research has shown that pharmacological GSK-3ß inhibition favors myogenic differentiation and plays an important role in modulating inflammatory processes. Isolecanoric acid (ILA) is a natural product isolated from a fungal culture displaying GSK-3ß inhibitory properties. The present study aimed to investigate the proregenerative and anti-inflammatory properties of this natural compound in the DMD context. Our results showed that ILA markedly promotes myogenic differentiation of myoblasts by increasing ß-Catenin signaling and boosting the myogenic potential of mouse and human stem cells. One important finding was that the GSK-3ß/ß-Catenin pathway is altered in dystrophic mice muscle and ILA enhances the myofiber formation of dystrophic MuSCs. Treatment with this natural compound improves muscle regeneration of dystrophic mice by, in turn, improving functional performance. Moreover, ILA ameliorates the inflammatory response in both muscle explants and the macrophages isolated from dystrophic mice to, thus, mitigate fibrosis after muscle damage. Overall, we show that ILA modulates both inflammation and muscle regeneration to, thus, contribute to improve the dystrophic phenotype.

Understanding Epicardial Cell Heterogeneity during Cardiogenesis and Heart Regeneration.

The outermost layer of the heart, the epicardium, is an essential cell population that contributes, through epithelial-to-mesenchymal transition (EMT), to the formation of different cell types and provides paracrine signals to the developing heart. Despite its quiescent state during adulthood, the adult epicardium reactivates and recapitulates many aspects of embryonic cardiogenesis in response to cardiac injury, thereby supporting cardiac tissue remodeling. Thus, the epicardium has been considered a crucial source of cell progenitors that offers an important contribution to cardiac development and injured hearts. Although several studies have provided evidence regarding cell fate determination in the epicardium, to date, it is unclear whether epicardium-derived cells (EPDCs) come from specific, and predetermined, epicardial cell subpopulations or if they are derived from a common progenitor. In recent years, different approaches have been used to study cell heterogeneity within the epicardial layer using different experimental models. However, the data generated are still insufficient with respect to revealing the complexity of this epithelial layer. In this review, we summarize the previous works documenting the cellular composition, molecular signatures, and diversity within the developing and adult epicardium.

Pitx2 Differentially Regulates the Distinct Phases of Myogenic Program and Delineates Satellite Cell Lineages During Muscle Development.

The knowledge of the molecular mechanisms that regulate embryonic myogenesis from early myogenic progenitors to myoblasts, as well as the emergence of adult satellite stem cells (SCs) during development, are key concepts to understanding the genesis and regenerative abilities of the skeletal muscle. Several previous pieces of evidence have revealed that the transcription factor Pitx2 might be a player within the molecular pathways controlling somite-derived muscle progenitors' fate and SC behavior. However, the role exerted by Pitx2 in the progression from myogenic progenitors to myoblasts including SC precursors remains unsolved. Here, we show that Pitx2 inactivation in uncommitted early myogenic precursors diminished cell proliferation and migration leading to muscle hypotrophy and a low number of SCs with decreased myogenic differentiation potential. However, the loss of Pitx2 in committed myogenic precursors gave rise to normal muscles with standard amounts of SCs exhibiting high levels of Pax7 expression. This SC population includes few MYF5+ SC-primed but increased amount of less proliferative miR-106b+cells, and display myogenic differentiation defects failing to undergo proper muscle regeneration. Overall our results demonstrate that Pitx2 is required in uncommitted myogenic progenitors but it is dispensable in committed precursors for proper myogenesis and reveal a role for this transcription factor in the generation of diverse SC subpopulations.

Regulation of Epicardial Cell Fate during Cardiac Development and Disease: An Overview.

The epicardium is the outermost cell layer in the vertebrate heart that originates during development from mesothelial precursors located in the proepicardium and septum transversum. The epicardial layer plays a key role during cardiogenesis since a subset of epicardial-derived cells (EPDCs) undergo an epithelial-mesenchymal transition (EMT); migrate into the myocardium; and differentiate into distinct cell types, such as coronary vascular smooth muscle cells, cardiac fibroblasts, endothelial cells, and presumably a subpopulation of cardiomyocytes, thus contributing to complete heart formation. Furthermore, the epicardium is a source of paracrine factors that support cardiac growth at the last stages of cardiogenesis. Although several lineage trace studies have provided some evidence about epicardial cell fate determination, the molecular mechanisms underlying epicardial cell heterogeneity remain not fully understood. Interestingly, seminal works during the last decade have pointed out that the adult epicardium is reactivated after heart damage, re-expressing some embryonic genes and contributing to cardiac remodeling. Therefore, the epicardium has been proposed as a potential target in the treatment of cardiovascular disease. In this review, we summarize the previous knowledge regarding the regulation of epicardial cell contribution during development and the control of epicardial reactivation in cardiac repair after damage.

Muscle Satellite Cell Heterogeneity: Does Embryonic Origin Matter?

Muscle regeneration is an important homeostatic process of adult skeletal muscle that recapitulates many aspects of embryonic myogenesis. Satellite cells (SCs) are the main muscle stem cells responsible for skeletal muscle regeneration. SCs reside between the myofiber basal lamina and the sarcolemma of the muscle fiber in a quiescent state. However, in response to physiological stimuli or muscle trauma, activated SCs transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent evidence has stated that SCs display functional heterogeneity linked to regenerative capability with an undifferentiated subgroup that is more prone to self-renewal, as well as committed progenitor cells ready for myogenic differentiation. Several lineage tracing studies suggest that such SC heterogeneity could be associated with different embryonic origins. Although it has been established that SCs are derived from the central dermomyotome, how a small subpopulation of the SCs progeny maintain their stem cell identity while most progress through the myogenic program to construct myofibers is not well understood. In this review, we synthesize the works supporting the different developmental origins of SCs as the genesis of their functional heterogeneity.