How do stem cells know what to become?
Nearly three decades after scientists isolated the first human embryonic stem cells, researchers are still working hard to understand precisely how a single, undifferentiated cell can become any one of the roughly 200 cell types that make up the human body.
A new study offers key insights, describing how cellular storage units known as "P bodies" heavily influence a cell's fate. By manipulating P bodies, the scientists were able to efficiently create hard-to-develop cell types in the lab, including "germ cells" (the cells that precede sperm and egg) and "totipotent" cells, which can become any type of cell in the body.
"I like to think of it as cellular alchemy," said Justin Brumbaugh, co-senior author and assistant professor of Molecular, Cellular and Developmental Biology at CU Boulder. "If we can understand how to manipulate cell fate— to drive one type of cell to become another type of cell— a whole world of applications opens up. Our paper sets the foundation for that."
The findings, published October 28 in the journal Nature Biotechnology , could help advance understanding of how embryos form and disease originates. They could also open new avenues for developing fertility treatments, regenerating organs and testing new drugs, said co-senior author Bruno Di Stefano, an assistant professor at the Stem Cell and Regenerative Medicine Center at Baylor College of Medicine.
"There is great value in understanding, at the most basic level, how biology works," Di Stefano said.
Cracking open the vaults
For the study, the research team examined embryonic human, mouse and chicken stem cells as they moved through various stages of differentiation. They zeroed in on P bodies, or processing bodies, clusters of Ribonucleic Acid (RNA) and protein found in the cytoplasm of cells across a variety of vertebrate species.
CU Boulder Biochemistry Professor Roy Parker discovered P bodies in 2003. Since then, studies have associated P body dysregulation with disease, including Parkinson's and certain cancers.
Scientists previously believed P bodies served as a sort of junk drawer for the cell, where RNA—the instructional molecule that tells a cell which genes to express—was hidden away and degraded when unused.
The new study found that P bodies are more like organized storage bins than a junk drawer, with different cell types holding different types of RNA that, if released, would have guided the cell toward a different fate.
"Our work shows that P-bodies sequester the products of certain genes to dampen their function and direct cell identity changes," said Brumbaugh.
Critically, the researchers found that if they perturbed the P bodies, or broke open the storage container, they could make those instructions readable again and rewind the cells to a previous, more malleable, developmental stage.
If you think of the stages of development as an upside-down tree, with a single cell at the top, moving down through a trunk, and branching out into more and more specialized cells (skin, lung, neuron, etc.), the researchers were able to guide cells at the tips of the branches back to the trunk where they could be more easily nudged to become something else.
In doing so, they were able to efficiently guide more mature cells to become primordial germ-cell-like cells (PGCLCs), lab grown cells that mimic germ cells, or totipotent-like cells.
"Totipotent-like cells are sort of the holy grail for stem cell biology," said Brumbaugh. "Being able to make these cell types and study them is something that's been extremely challenging."
Potential ramifications for human health
The researchers imagine a day when germ cells developed in a lab via this process could form sperm or eggs to assist with new fertility treatments.
And, theoretically, totipotent cells, derived from something as simple as a skin cell, could be used to regenerate organs or tissues ravaged by disease.
In the shorter term, early-development cells generated in the lab could be invaluable for understanding the origins of disease.
For example, scientists could take a neuron from a person with Parkinson's disease, nudge it back to its earliest developmental stages and examine what went wrong. Or they could examine lab-grown germ cells to explore what might drive infertility or birth defects.
Drug developers could also use such cells to create specialized tissue for drug testing, researchers said.
The study also found that noncoding RNAs called microRNAs play a critical role in determining which RNAs get stored inside the P bodies. Modulating these microRNAs could lead to new therapies.
More research is already underway.
"It's exciting to understand how things work," said Di Stefano. "Now that we know what drives this process, we can manipulate it."
