Inhibition of JAK-STAT signaling stimulates adult satellite cell function

Abstract

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of murine adult satellite cells to contribute to regeneration and repopulate the niche. Gene expression analysis identified an increase in expression of JAK/STAT signaling targets between 3 week old and 18 month old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Knockdown of Jak2 or Stat3 in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche. Pharmacological inhibition of Jak2 and Stat3 similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a dramatic enhancement of muscle repair and force generation. Together these results reveal intrinsic properties that functionally distinguish adult satellite cells and suggest a promising therapeutic avenue for the treatment of muscle wasting diseases.

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

“…The discovery of murine MuSCs capable of robustly regenerating and restoring strength to injured muscles (1,3,7,(16)(17)(18)(19), and a means for their expansion in culture using inducers such as p38 MAPK inhibitors, has provided a framework for their future clinical application (22,(51)(52)(53). Moreover, recent strides in the isolation and characterization of their human counterparts from tissues or as derivatives from human embryonic stem (ES) or induced pluripotent stem (iPS) cells (54-59) now facilitate the use of these potent cell types as a muscle cell therapeutic.…”

Acute and Temporal Expression of Tumor Necrosis Factor (TNF)-α-stimulated Gene 6 Product, TSG6, in Mesenchymal Stem Cells Creates Microenvironments Required for Their Successful Transplantation into Muscle Tissue

“…CD44 activated by ligand binding is internalized and elicits STAT3 (signal transducer and activator of transcription 3) acetylation (47). Price et al (48) currently reported that JAK-STAT3 signaling triggered the myogenic differentiation through cyclin D1 promoter. Despite short time expression of TSG6 in MSCs, the SHAP-HA complex remained longer in the transplanted area suggesting that the SHAP-HA complex may play a role in myogenic differentiation of MSCs (see fetal actin-stained muscle fibers in Fig.…”

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…It has also been reported that inhibition of the IL-6 intracellular mediator, namely the Jak/Stat pathway, stimulates muscle regeneration in both aged and dystrophic mice [60,61].…”