Muscle satellite cells (MuSCs) play a vital role in skeletal muscle regeneration. However, in intractable muscle diseases such as volumetric muscle loss (VML), the quantity and function of MuSCs are significantly reduced, severely limiting the body's inherent muscle regeneration capability. In this study, we propose a novel strategy to modulate the fate of MuSCs using a combination of bioactive magnesium (Mg) and silicon (Si) ions, sustainably delivered through magnesium silicate (MgSiO3, MS) bioceramic-based scaffolds. In vitro, Mg and Si ions synergistically promote the proliferation and differentiation of MuSCs. Similarly, Mg and Si ions derived from MS/poly (L-lactic acid) (MS/PLLA) composite scaffold also increases the proliferation and differentiation ability of MuSCs. Furthermore, MS/PLLA composite scaffolds facilitate the activation of MuSCs, regeneration of muscle fiber, and neovascularization, while inhibiting fibrosis, thereby effectively restoring muscle function and promoting tibialis anterior muscle functional regeneration in a VML mouse model. Mechanistically, the combination of Mg and Si ions promotes the activation and proliferation of MuSCs by activating the Notch1-Hes1 pathway. Besides, the combination of Mg and Si ions also improves the differentiation of MuSCs by up-regulating Myod and Myog, and enhances fusion by up-regulating Mymk and Mymx expression. The outcomes of our research introduce a promising approach to the treatment of skeletal muscle injuries and related diseases.
Ningbo Cai,Bingtian Xu,Xing Li,Yunyun Qin,Mengfan Li,Kechun Chen,Jiangping Xu,Haitao Wang
The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia . Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 μM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo . Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.
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