Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species
Sahar Tavakoli,
Vivian Garcia,
Eric Gähwiler,
Isaac Adatto,
Apoorva Rangan,
Kathleen A. Messemer,
Sara Ashrafi Kakhki,
Song Yang,
Victoria S. Chan,
Margot E. Manning,
Haleh Fotowat,
Yi Zhou,
Amy J. Wagers,
Leonard I. Zon
Affiliations
Sahar Tavakoli
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
Vivian Garcia
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Eric Gähwiler
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Institute for Regenerative Medicine, University of Zurich, ETH Zurich, Zurich, Switzerland
Isaac Adatto
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
Apoorva Rangan
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Stanford Medicine, Stanford University, Stanford, CA 94305, USA
Kathleen A. Messemer
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Sara Ashrafi Kakhki
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA
Song Yang
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
Victoria S. Chan
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
Margot E. Manning
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
Haleh Fotowat
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
Yi Zhou
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA
Amy J. Wagers
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; Joslin Diabetes Center, Boston, MA 02215, USA; Corresponding author
Leonard I. Zon
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; Howard Hughes Medical Institute, Boston, MA 02115, USA; Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
