杜氏肌营养不良（duchenne muscular dystrophy）是最常见的致死性儿童遗传病，患者由于缺乏抗肌萎缩蛋白（dystrophin），肌肉不断退化，患儿早年发病后逐渐失去运动能力，通常在20岁左右死于心脏衰竭或呼吸衰竭。目前世上还没有办法逆转或治愈这种疾病。近年来，研究人员不断尝试各种方法诱导人类多能性干细胞生产骨骼肌干细胞，使其在活肌肉中发挥作用，再生肌纤维。然而，此前一直无法产生成熟细胞，导致干细胞替代疗法治疗杜氏的策略收效甚微。
近日，来自加州大学洛杉矶分校的研究人员开发了一种新型的有效分离和移植人类多能干细胞生成骨骼肌细胞的新策略。该研究基于人类自然发育进程，研制了一套可在实验室诱导成熟肌肉细胞的方法，这些恢复抗肌萎缩蛋白生产能力的肌细胞能修复杜氏肌营养不良患儿的肌肉健康。通过分析人类发育，研究人员发现一种胎儿骨骼肌细胞具有非比寻常的再生能力，进一步探索发现，这种胎儿肌细胞携带两种新细胞表面标记，即ERBB3和NGFR，利用这两种标志物，研究人员准确地将它们从人体组织和诱导多能干细胞中分离出来。接着，这些被分离出来的细胞被诱导成熟直至产生抗肌萎缩蛋白生产的肌纤维（dystrophin-producing muscle fibers），随后被注射入患病小鼠体内，同时用TGF-β抑制剂处理小鼠，结果有效改善了小鼠骨骼肌形成和运动能力。
研究人员表示，该研究首次在实验室中建立了骨骼肌细胞并具有完整功能性，为杜氏肌营养不良的干细胞疗法提供了支持。
推荐阅读原文：
ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs.
Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite cells remains unclear. We observed that hPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Using RNA sequencing, we found that the cell surface receptors ERBB3 and NGFR demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of transforming growth factor-β signalling during differentiation improved fusion efficiency, ultrastructural organization and the expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibres after engraftment of CRISPR-Cas9-corrected Duchenne muscular dystrophy human induced pluripotent stem cell-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels that are equal to directly isolated human fetal muscle cells.
