Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species

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. [Display omitted] •Cross-species discovery approach for examining chemical activity to enhance engraftment•LPA and NFA increase the engraftment efficiency of myogenic progenitor cells•Increase in intracellular Ca2+ induces the engraftment of myogenic progenitor cells•Engrafted skeletal muscle cells rescue zebrafish model of Duchenne muscular dystrophy Tavakoli et al. perform a cross-species in vivo screen to directly test chemicals for enhanced muscle progenitor cell engraftment. Their findings show that a short ex vivo pre-transplantation treatment with specific compounds is beneficial, improving the engraftment of myogenic progenitor cells and improving cell therapy as a treatment option for degenerative muscle disorders.