A new study reveals that reprogramming specialized cells to become different types of cells, a key process in regenerative medicine, faces a major hurdle. The challenge lies in the DNA methylation patterns of the cells, which are like cellular "memory" markers. This study reveals that these patterns often prevent reprogrammed cells from fully adopting their new identities, limiting their effectiveness for long-term treatments. The study provides new insights into these limitations and could help develop better methods for cell transformation in medical applications.
A new study led by Professors Yosef Buganim and Howard Cedar from Hebrew University and Professor Ben Stanger from Pennsylvania University has shed new light on the challenges of converting one type of specialized cell into another, a process critical for advances in regenerative medicine. Despite recent progress, researchers have discovered that a key obstacle in maintaining the new identity of reprogrammed cells lies in their original DNA methylation patterns – crucial markers that define cell identity.
Cellular reprogramming, often achieved through a process known as trans-differentiation, allows scientists to transform cells into different types, such as turning skin cells into heart cells. While these transformations initially appear successful, the newly reprogrammed cells frequently fail to maintain their new identity over time. The result? Cells that behave only partially like the target cell type, limiting their use in long-term treatments or therapeutic applications.
To better understand this issue, the researchers developed a novel approach to analyze changes in DNA methylation during cell conversion. DNA methylation is a chemical process that helps regulate which genes are active in a cell, serving as a sort of cellular memory that locks in a cell’s identity. By studying various models of direct cell conversion in both lab-grown cells and animal tissues, the team discovered that, although the cells may begin to look and act like their new type, they retain their original DNA methylation patterns.
"Despite significant changes in gene expression, the reprogrammed cells are unable to fully erase their original developmental instructions. This limits their ability to fully embrace their new role," explained Professor Buganim.
The study suggests that the developmental constraints embedded in the regulatory regions of DNA prevent cells from resetting these patterns. As a result, reprogrammed cells fall short of becoming fully functional versions of their intended type.
"This discovery opens up new avenues in understanding the molecular barriers to complete cellular reprogramming," added Professor Cedar. "It also brings us one step closer to figuring out how to overcome these roadblocks, which could have significant implications for future medical applications, including tissue regeneration and disease modeling."
These findings mark an important step in the field of cellular reprogramming, offering crucial insights into how to achieve stable and functional cell transformations for future cell-based therapy.
The research paper titled “Transdifferentiation occurs without resetting development-specific DNA methylation, a key determinant of full-function cell identity” is now available at PNAS and can be accessed at https://journals.sagepub.com/doi/epub/10.1177/10870547241280607
Researchers:
Ahmed Radwan1, Jason Eccleston2, Ofra Sabag1, Howard Marcus1, Jonathan Sussman2, Alberto Ouro1, Moran Rahamim1, Meir Azagury1, Batia Azria1, Ben Z. Stanger2, Howard Cedar1 and Yosef Buganim1
Institution:
- Department of Developmental Biology and Cancer Research Institute for Medical Research Israel-Canada, Hebrew University Medical School
- Departments of Medicine and Cell and Development Biology, The Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania
The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 81st according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en
