Researchers have identified differences in human stem cells that illustrate how an individual’s cells may uniquely influence their ‘developmental dance’ at the molecular level, which in turn affects the formation of the brain and body.
A team from the Johns Hopkins University School of Medicine has explored variations in human stem cells, shedding light on how these differences may dictate a person’s distinct “developmental dance” at a molecular level, thus directing the development of the brain and body. These discoveries enhance our comprehension of how cellular variations arise among individuals and could lead to personalized medical treatments and strategies to repair damaged or diseased organs.
Published on September 10 in Stem Cell Reports, the research utilized human induced pluripotent stem cells (iPSCs), which are akin to cells from early embryonic stages capable of turning into various tissue types. By examining pluripotent cells from multiple donors, researchers uncovered how genetic and epigenetic factors (non-DNA related changes) contribute to individual differences in the early stages of brain development.
“Every human body originates from a single cell, and as the cells divide in the developing embryo, they follow a genetically-driven choreography to form the new human,” explains Carlo Colantuoni, Ph.D., who is an assistant professor in the neurology and neuroscience departments at Johns Hopkins University School of Medicine.
However, Colantuoni points out that, although this ‘developmental dance’ contains fundamental steps that are common across humans (and other animals), the study has revealed molecular patterns and gene expression characteristics that modify these universal steps, leading to individual development.
In this research, scientists from Johns Hopkins University and Yale University employed a method called “cellular reprogramming,” which enables mature cells to revert back to an embryonic state—a groundbreaking technique recognized with a Nobel Prize in 2012. Specifically, they transformed skin cells from adults back into an early embryonic form. These induced pluripotent stem cells (iPSCs) hold the potential to differentiate into any cell type within the human body.
After allowing the iPSCs to grow and interact freely, the cells began to express their innate nature and individuality. RNA sequencing, a method that measures the activity level of genes through the production of RNA, provided researchers with a detailed molecular view of the cells’ functions. By correlating the RNA data from the iPSCs with data from developing mouse embryos, the researchers traced the variations of the donor cells onto a framework of mammalian development, facilitating the observation of systematic differences in how individual human cells progress through early development—similar patterns identified in data from 100 human stem cell donors.
The scientists discovered two distinct patterns, or rhythms, from the RNA data. The first type was universally consistent across all donors, representing major modules responsible for the development of key human organs, such as the brain, heart, and liver. The second type was subtler, more evolutionarily recent, and unique to certain individuals, regardless of the cells’ eventual functions.
Interestingly, these individual variations observed in the laboratory settings were also apparent in the mature cells of the donors, indicating that these unique cellular development patterns have significant implications for each individual’s growth journey.
The researchers believe that their findings suggest these unique cellular patterns not only exemplify the distinct pathways of an individual’s development but also signify potential indicators of a person’s lifelong health and disease risks. Colantuoni mentions that these insights could lead to more tailored approaches in regenerative medicine.
“We propose that studying induced pluripotent stem cells and their derivatives can help identify each patient’s risk factors for complex diseases and determine the most effective personalized treatments,” states Colantuoni. “We envision a future where a patient’s comprehensive medical history, genomic data, and living cells are integrated to accurately diagnose and customize medical care.”
Colantuoni emphasizes that scientists are only starting to comprehend the specific molecular mechanisms that underlie the variations in human cellular development. Additional studies with broader and more diverse donor populations are necessary to fully understand the long-term health consequences of the unique trajectories of an individual’s developing cells.
Additional contributors to this research include Suel-Kee Kim, Seungmae Seo, Genevieve Stein-O’Brien, Amritha Jaishankar, Kazuya Ogawa, Nicola Micali, Yanhong Wang, Thomas Hyde, Joel Kleinman, Elana Fertig, Joo Heon Shin, Daniel Weinberger, Joshua Chenoweth, Daniel Hoeppner, and Ronald McKay.
Financial support for this study was provided by NCI/NIH grants R01CA177669, P30CA006973, U01CA212007, and U01CA253403, along with the Johns Hopkins University Catalyst Award, which includes EJF R01NS116418, R01HG010898, MH116488, and U01MH124619, awarded to N.S. Data sharing and visualization through NeMO Analytics were backed by grants R24MH114815 and R01DC019370.
