Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Cell Rep. 2023 Apr 25;42(4):112365. doi: 10.1016/j.celrep.2023.112365. Epub 2023 Apr 4.
Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited by the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small-molecule screening platform employing zebrafish and mice, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to discriminate those that could increase myogenic engraftment in vivo in zebrafish and mice. This effort identified two lipids, lysophosphatidic acid and niflumic acid, both linked to the activation of intracellular calcium-ion flux, which showed conserved, dose-dependent, and synergistic effects in promoting muscle engraftment across these vertebrate species.
干细胞移植为骨骼肌遗传疾病提供了一种潜在的治愈策略，但该方法受到体外细胞扩增的有害影响和随后较差的植入效率的限制。为了克服这一限制，我们试图确定能增强培养的肌肉祖细胞的成肌活性的分子信号。在这里，我们报告了一种使用斑马鱼和小鼠的跨物种小分子筛选平台的开发和应用，该平台能够快速、直接评估化合物对移植肌肉前体细胞植入的影响。使用该系统，我们筛选了生物活性脂质文库，以区分那些能在斑马鱼和小鼠体内增加成肌植入的脂质。这项研究确定了两种脂质，溶血磷脂酸和尼氟酸，它们都与细胞内钙离子流的激活有关，这两种脂质在促进这些脊椎动物物种的肌肉植入方面表现出保守的、剂量依赖性的和协同作用。
