SAN FRANCISCO—April 30, 2026—Years before he conducted the research that would earn him a Nobel Prize in Physiology and Medicine, Shinya Yamanaka, MD, PhD, was a postdoctoral scientist at Gladstone Institutes, studying genes. There, he helped discover a gene (now called eIF4G2) that's essential for early embryonic development.
Then, the story pauses. Without the technology needed to develop an animal model to further investigate the gene, Yamanaka moved on to develop induced pluripotent stem (iPS) cells—adult cells that have been reprogrammed into an embryonic state. That work earned him the Nobel Prize, but he never forgot his first gene.
Now, 30 years since his postdoc, Yamanaka has circled back to eIF4G2.
In a study published in the journal Cell Stem Cell, he and his colleagues finally created a sophisticated animal model to study the gene. With that tool, they've now shown that eIF4G2 is indispensable for adult intestinal health.
"We showed this gene ensures adult intestinal stem cells remember they're adult cells and don't revert to a more fetal-like state, so they can produce the specialized cells needed for digestion and fighting germs," says Yamanaka, L.K. Whittier Foundation Investigator in Stem Cell Biology at Gladstone and senior author of the study. "Our findings also provide new clues for how we might one day control cellular reprogramming for therapy."
A Critical Model
In the late 1990s, Yamanaka found that mice without the gene eIF4G2 died as embryos. So, he knew it was important, but the limited technology at the time made it impossible to study what happened to adult mice lacking this gene, meaning he couldn't pinpoint its exact role.
In the new study, he and his team used CRISPR gene editing technology to create the first adult mouse to lack eIF4G2. They found a way to incorporate a genetic switch that removed the gene only after the mice had reached adulthood.
"For a long time, we didn't understand the function of this gene," Yamanaka says. "Finally, we've created a good model that allows us to address long-unanswered questions about what the gene does in the body."
A Gene That Keeps Stem Cells on Track
Embedded in the intestinal wall, adult stem cells are hard at work, maintaining and repairing the intestine over a lifetime. These cells divide and transform into more specialized cells, regenerating the intestinal lining every few days.
With the new model, Yamanaka's team was able to look at what would happen to intestinal stem cells after losing the gene eIF4G2.
They found that eIF4G2 helps cells product a wide range of proteins. So, when the gene is lost, the production of many proteins is reduced. Importantly, a small subset of critical proteins drops below a threshold level, which appears to drive the loss of adult stem cell identity; they stop functioning properly and revert to a state similar to that of a developing embryo.
This phenomenon has been seen before in biology. When the intestine is severely damaged by radiation or chemotherapy, for instance, adult intestinal stem cells are lost. To compensate for the deficiency, specialized adult cells will temporarily become more like stem cells to help rebuild tissues and restore intestinal function.
"We've seen the body naturally use a fetal-like state as a repair mode, but this is usually a temporary reaction and the cells eventually go back to their normal jobs," says Haruko Kunitomi, MD, PhD, a scientist in Yamanaka's lab and first author of the study. "What we found is that without eIF4G2, the stem cells stay stuck in this primitive state."
Insights for Regenerative Medicine
The scientists showed that without eIF4G2, as intestinal stem cells revert back to an embryonic-like state, the physical architecture of the intestine remains relatively intact for months.
But the stem cells are unable to mature into functional adult tissue, which means the intestine doesn't have as many of the specialized cells it needs to function properly. And, the stem-cell compartments of the intestine become dominated by immature cells, which offered the team a clearer view of how cells shift between adult and developmental states.
Previously, genes like eIF4G2 that are involved in making other proteins were viewed as "housekeepers" that support fundamental cellular functions required for cell survival. But this study shows they're actually precision tools that can be used to control a cell's identity.
"Stem cells need precise regulation to become other cell types, such as the ones that populate the intestinal lining," Kunitomi says. "We showed that this is more than a housekeeping process, but also a mechanism that provides a steady supply of certain proteins to keep stem cells in their proper state."
While this study focused on the intestine, eIF4G2 is found in tissues throughout the body. Thanks to their new animal model, the scientists now plan to investigate the gene's specific function in bone marrow, the heart and other cell types.
The findings also provide major insights into regenerative medicine by shedding light on how the body manages the transition between mature cells and a fetal-like state for the purpose of repair.
"Our new model makes it easy to observe a process that's normally chaotic and temporary, and to study exactly how tissues reprogram themselves during healing," Yamanaka says. "It opens up a new path for regenerative therapies that could target the production of proteins to tell a cell what to become."
About the Study
The paper, " eIF4G2-Mediated Selective Translation of Chromatin Regulators Safeguards Adult Intestinal Stem Cell Identity and Differentiation, " was published in the journal Cell Stem Cell on April 30, 2026. The authors are Haruko Kunitomi, Aye Myat Khaine, Radia Jamee, Vanessa Arreola, Mariselle Lancero, Amba Raychaudhuri, Samuel Perli, Kiichiro Tomoda, and Shinya Yamanaka of Gladstone; Yoshiko Sato and Mio Iwasaki of the Center for iPS Cell Research and Application; Pedro Ruivo of UC Davis; Mari Mito, Yuichi Shichino, and Shintaro Iwasaki of RIKEN.
The work was supported by the Japan Agency for Medical Research and Development/AMED (JP21bm0104001, JP20gm1410001, JP23gm6910005), KAKENHI (JP24H02307), the iPS Cell Research Fund, RIKEN Pioneering Projects, the Core Center for iPS Cell Research, Research Center Network for Realization of Regenerative Medicine, the Kyoto University On-Site Laboratory Initiative, Hiroshi Mikitani, Marc Benioff, the L. K. Whittier Foundation, the Roddenberry Foundation, and Gladstone Institutes.
About Gladstone Institutes
Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.
