Stem cells are the blank slate on which all the specialized cells in our bodies are built, and finding ways to revert adult cells back to that stage can help fight a whole range of illnesses. A breakthrough came about 10 years ago when researchers discovered that skin cells could be “reprogrammed” into stem cells by adding certain genes into their DNA, but now scientists at the Scripps Research Institute have found human antibodies that can perform the same function from the outside.
A groundbreaking 2006 study found that fibroblasts – cells found in the skin and connective tissue – could be reverted back into stem cells by introducing four transcription factor genes, Oct4, Sox2, Klf4 and c-Myc (OSKM), into the nucleus of the cell. While this technique has been a useful way to create induced pluripotent stem cells (IPSCs) for a variety of medical purposes, it still has its risks. There’s a chance the affected cells can turn cancerous for one, but even if they don’t, their properties aren’t always consistent.
So the Scripps researchers set out to find more natural pathways to changing a cell’s identity, without needing to insert any extra DNA. Antibodies are a promising avenue, since they bind to proteins on the surface of the cell and can perform similar functions to the transcription factor genes.
The team started by collecting a library of 100 million human antibodies, and then scanned through it to find any that could potentially replace the OSKM transcription factors. First, they grew mouse fibroblast cells in culture, then inserted two of the usual genes, Oct4 and Klf4. Then, they added the whole library of antibody genes to the cell culture, to find any that could replace the function of the other two transcription factors, Sox2 and c-Myc.
Sure enough, some of those adult cells turned into stem cells. The team could then find out which antibodies triggered that response by sequencing the DNA of the IPSCs they created. In another set of tests, the team used that same process to find antibodies to replace Oct4.
“This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties,” says Kristin Baldwin, senior author of the study.
The work has also shed some light on the functions of certain genes that have been linked to cancer, such as Wilms tumor 1 (WT1). Unfortunately, in this study the researchers weren’t able to find an antibody substitute for the fourth transcription factor, Klf4. That’s the subject of future work, the team says, along with testing the process on human cells instead of those from mice.