A team from the Massachusetts General Hospital, Center for Regenerative Medicine (MGH-CRM), and the Harvard Stem Cell Institute (HSCI) genetically engineered a mouse entirely from induced pluripotent stem cells (iPSCs). Previously, complete animals have only been created from embryonic stem cells, which have a greater developmental potential than most iPSCs.
Led by Konrad Hochedlinger, professor in the department of stem cells and regenerative medicine at Harvard University, the experiment is part of their larger investigation to improve the developmental potential of iPSCs to match their embryonic counterparts by comparing gene expression.
While comparing the gene expression in mouse embryonic stem cells and mouse iPSCs, the researchers discovered a significant difference in the gene expressed by the two cell types.
"We found that a segment of chromosome 12, containing genes important for fetal development, was abnormally shut off in most iPSCs," Hochedlinger said in a press release. "These findings indicate we need to keep improving the way we produce iPSCs and suggest the need for new reprogramming strategies." Because this segment of the genome was not expressed, the iPSCs failed to generate any live mice.
But Hockedlinger’s team did find the chromosome 12 cluster active in one iPSC line out of the 60 iPSC lines that they developed from different types of mouse adult cells. From this cell line, the researchers developed a live mouse with the same efficiency as the embryonic cells.
"The activation status of this imprinted cluster allowed us to prospectively identify iPSCs that have the full developmental potential of embryonic stem cells," said Matthias Stadtfeld, a researcher in Hochedlinger’s laboratory. "Identifying pluripotent cells of the highest quality is crucial to the development of therapeutic applications, so we can ensure that any transplanted cells function as well as normal cells.”
According to Stadtfeld, the researchers will investigate whether human iPSCs have similar differences in gene expression, and if those differences can be manipulated to create patient-specific iPSCs for clinical use.
Funding for this research was provided by Hochedlinger’s Director’s Innovator Award from the National Institutes of Health, and his Early Career Scientist award from the Howard Hughes Medical Institute. Additional support was provided by the Schering Foundation, the Jane Coffin Children Memorial Fund, and Sanofi-Aventis. The paper, “Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells,” was published April 25, in Nature.