We can’t turn back time, but scientists have developed a method for ‘rewinding’ adult cells back to the stem cell-like states they were in during embryonic development. This process, known as reprogramming, carries immense potential in the field of regenerative medicine—patients could one day receive reprogrammed cells (of their own) to treat diseased tissues.
However, while cell reprogramming can be initiated, scientists have found it difficult to control the biological outcomes. Reprogrammed cells can take a multitude of possible routes on their way towards their final states, explained Jonathan Yuin-Han Loh, a Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), and a co-corresponding author on the study. Ultimately, using current methodologies, only a few of these cells successfully become reprogrammed, significantly limiting the use of this technique for clinical applications.
In a step towards enhancing reprogramming efficiency, Loh and colleagues aimed to map the molecular mechanisms at play during this process. The scientists used advanced single-cell sequencing technologies to analyze individual human cells, sampled at various stages of their reprogramming journeys.
“Most of the previous studies are based on bulk measurement of a heterogeneous population, which mask the signals from rare, reprogrammed populations,” said Loh, who added that conventional methods often miss the tiny fraction of successfully reprogrammed cells. “Single-cell approaches allow us to investigate molecular events occurring within every individual cell.”
The team found three distinct subpopulations of cells that emerged early on during the reprogramming process, each of which had a different propensity for reverting to a stem cell-like state. Critically, they also identified specific molecular markers associated with each of these subpopulations, key features required for isolating cells with the greatest chances of becoming reprogrammed.
Additionally, the researchers uncovered a relationship between two molecular regulators of cell fate, FOSL1 and TEAD4. Activation of the transcription factor FOSL1 suppressed reprogramming. Conversely, turning off FOSL1 triggered the expression of TEAD4—the green light for cells to go down the reprogramming path. “A binary choice between FOSL1- and TEAD4-centric regulatory networks determines the outcome of a successful reprogramming,” said study first author Qiaorui Xing, a researcher at IMCB.
Together, these findings serve as a roadmap for tracking the trajectories of reprogrammed cells and could help propel stem cell therapies towards the clinic. In follow-up studies, Loh and colleagues plan to take a closer look at the role of transiently activated genes in reprogramming, to determine whether they could exploit these pathways to further boost reprogramming efficiencies.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB), Singapore Bioimaging Consortium (SBIC), and Institute of Bioengineering and Nanotechnology (IBN).
