Case Western Reserve researchers have discovered landmarks within pluripotent stem cells that guide how they develop to serve different purposes within the body. This breakthrough offers promise that scientists eventually will be able to direct stem cells in ways that prevent disease or repair damage from injury or illness. The study and its results appear in the June 5 edition of the journal Cell Stem Cell.
Pluripotent stem cells are so named because they can evolve into any of the cell types that exist within the body. Their immense potential captured the attention of two accomplished faculty with complementary areas of expertise.
“We had a unique opportunity to bring together two interdisciplinary groups,” said co-senior author Paul Tesar, PhD, Assistant Professor of Genetics and Genome Sciences at CWRU School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor.
"We have exploited the Tesar lab’s expertise in stem cell biology and my lab’s expertise in genomics to uncover a new class of genetic switches, which we call seed enhancers,” said co-senior author Peter Scacheri, PhD, Associate Professor of Genetics and Genome Sciences at CWRU School of Medicine. “Seed enhancers give us new clues to how cells morph from one cell type to another during development."
The breakthrough came from studying two closely related stem cell types that represent the earliest phases of development — embryonic stem cells and epiblast stem cells, first described in research by Tesar in 2007. “These two stem cell types give us unprecedented access to the earliest stages of mammalian development,” said Daniel Factor, graduate student in the Tesar lab and co-first author of the study.
Olivia Corradin, graduate student in the Scacheri lab and co-first author, agrees. “Stem cells are touted for their promise to make replacement tissues for regenerative medicine,” she said. “But first, we have to understand precisely how these cells function to create diverse tissues.”
Enhancers are sections of DNA that control the expression of nearby genes. By comparing these two closely related types of pluripotent stem cells (embryonic and epiblast), Corradin and Factor identified a new class of enhancers, which they refer to as seed enhancers. Unlike most enhancers, which are only active in specific times or places in the body, seed enhancers play roles from before birth to adulthood.
They are present, but dormant, in the early mouse embryonic stem cell population. In the more developed mouse epiblast stem cell population, they become the primary enhancers of their associated genes. As the cells mature into functional adult tissues, the seed enhancers grow into super enhancers. Super enhancers are large regions that contain many enhancers and control the most important genes in each cell type.
“These seed enhancers have wide-ranging potential to impact the understanding of development and disease,” said Stanton Gerson, MD, Asa & Patricia Shiverick and Jane Shiverick (Tripp) Professor of Hematological Oncology and Director of the National Center for Regenerative Medicine at Case Western Reserve University. “In the stem cell field, this understanding should rapidly enhance the ability to generate clinically useful cell types for stem cell-based regenerative medicine.”
“Our next step is to understand if mis-regulation of these seed enhancers might play a role in human diseases,” Tesar said. “The genes controlled by seed enhancers are powerful ones, and it’s possible that aberrations could contribute to things like heart disease or neurodegenerative disorders.”
Scacheri added, “It is also clear that cancer can be driven by changes in enhancers, and we are interested in understanding the role of seed enhancers in cancer onset and progression.”
Other authors included Gabriel Zentner, PhD, of the Basic Sciences Division of the Fred Hutchinson Cancer Research Center, Alina Saiakhova of the Department of Genetics and Genome Sciences of Case Western Reserve University School of Medicine, Lingyun Song and Gregory Crawford, PhD, of the Institute for Genome Sciences & Policy of Duke University, and Josh Chenoweth, PhD, and Ronald McKay, PhD, of the Lieber Institute for Brain Development.
This research was supported by funding from the New York Stem Cell Foundation, the National Institutes of Health, the Mount Sinai Health Care Foundation, the Case Comprehensive Cancer Center and the Case Western Reserve University Cellular and Molecular Biology training grant.
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. case.edu/medicine.