A modified version of iPS methodology, called interrupted reprogramming, allows for a highly controlled, potentially safer, and more cost-effective strategy for generating progenitor-like cells from adult cells. As demonstrated in the journal Stem Cell Reports, the adult mouse respiratory tract cells called Club cells into large, pure populations of induced progenitor-like (iPL) cells, which retained a residual memory of their parental cell lineage and therefore generated mature Club cells. These cells showed potential as a cell replacement therapy in mice with cystic fibrosis.
"A major block in the critical path of regenerative medicine is the lack of suitable cells to restore function or repair damage," says co-senior author Tom Waddell. "Our approach starts with purifying the cell type we want and then manipulating it to give those cell types characteristics of progenitor cells, which can grow rapidly but produce only a few cell types. As such, it is much more direct, more rapid, and the batches of cells are more purified."
Despite significant progress, these protocols remain limited by low yield and purity of the desired mature cell types, as well as the potential of immature cells to form tumors. Moreover, there is no standardized approach applicable to all cell types, and the development of personalized therapies based on patient-derived pluripotent cells remains very expensive and time-consuming.
To address these issues, Waddell et al. developed an interrupted reprogramming strategy, which is a modified version of the iPS methodology. The researchers started to genetically reprogram adult Club cells isolated from mice, transiently expressing the four iPS reprogramming factors, but interrupted the process early, prior to reaching the pluripotent state, to generate progenitor-like cells, which are more committed to a specific lineage and show more controlled proliferation than pluripotent cells.
The researchers showed that the resulting Club-iPL cells could give rise to not only Club cells, but also to other respiratory tract cells such as mucus-secreting goblet cells and ciliated epithelial cells that produce the CFTR protein, which is mutated in patients with cystic fibrosis. When the Club-iPL cells were administered to CFTR-deficient mice, the cells incorporated into tissue lining the respiratory tract and partially restored levels of CFTR in the lungs without inducing tumor formation.
This technology can theoretically be applied to almost any cell type that can be isolated and purified, and isolation of highly purified populations of adult cells from most organs is already possible with existing techniques.
The approach could be used for a variety of regenerative medicine practices, including cell replacement therapy, disease modeling, and drug screening for human diseases. But there is still a long way to go before clinical translation. For their own part, the researchers plan to test this approach with other cell types, including human cells. They will also try to determine if there are safe ways to engraft these cells in human lungs.