Human induced pluripotent stem cells (hiPSCs) are a potential source for cell therapy of Duchenne muscular dystrophy. To reliably obtain skeletal muscle progenitors from hiPSCs, we treated hiPS cells with a Wnt activator, CHIR-99021 and a BMP receptor inhibitor, LDN-193189, and then induced skeletal muscle cells using a previously reported sphere-based culture. This protocol greatly improved sphere formation efficiency and stably induced the differentiation of myogenic cells from hiPS cells generated from both healthy donors and a patient with congenital myasthenic syndrome. hiPSC-derived myogenic progenitors were enriched in the CD57(−) CD108(−) CD271(+) ERBB3(+) cell fraction, and their differentiation was greatly promoted by TGF-β inhibitors. TGF-β inhibitors down-regulated the NFIX transcription factor, and NFIX short hairpin RNA (shRNA) improved the differentiation of iPS cell-derived myogenic progenitors. These results suggest that NFIX inhibited differentiation of myogenic progenitors. hiPSC-derived myogenic cells differentiated into myofibers in muscles of NSG-mdx4Cv mice after direct transplantation. Our results indicate that our new muscle induction protocol is useful for cell therapy of muscular dystrophies.
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness due to the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum (SR), but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. Administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for seven weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.
Arachnoid plasty using fibrin glue is suggested to be effective in preventing complications associated with SAH and aneurysmal surgery. A better outcome in the elderly patients can be achieved.
ObjectivesTo determine quantitatively the association between type 2 diabetes mellitus (T2DM) and disseminated intravascular coagulation (DIC).DesignRetrospective cohort study using a claims database.SettingMedical care institutions representing 9% of all secondary hospitals (acute care hospitals) in Japan.ParticipantsIn total, 797 324 admissions, comprising 435 354 patients aged 18–79 years at the time of admission, were enrolled between January 2010 and September 2014. All patients were diagnosed with diabetes or admitted to hospitals that provided laboratory data.Main outcome measuresIncidence of DIC reported by physicians in claims data.ResultsLogistic regression analysis found that the risk of DIC was significantly higher in T2DM patients than in non-DM patients (fully adjusted OR: 1.39 (95% CI 1.32 to 1.45)), independent of age, sex, admission year and potential underlying diseases. The higher risk of DIC in T2DM patients was apparent in those who were treated with insulin within the 30-day period prior to admission (1.53 (1.37 to 1.72)). When stratified by the potential underlying diseases, the risk of DIC was higher in T2DM patients with non-septic severe infection (1.67 (1.41 to 1.97)) and with solid tumour (1.59 (1.47 to 1.72)) than in non-DM patients with those underlying diseases. The risk was similar between T2DM and non-DM patients with sepsis (0.98 (0.90 to 1.08)) and lower in T2DM patients with acute leukaemia (0.70 (0.59 to 0.84)).ConclusionsT2DM was associated with a higher risk of DIC, particularly when recently treated with insulin, as well as among admissions with solid tumour or non-septic severe infection.
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