Mathematical model could bring us closer to effective stem cell therapies

The model could allow scientists to finally figure out the order of genetic operations inside developing cells.

11:00 AM

Author | Kelly Malcom

molecule protein microscopic blue orange
Getty Images

Stem cells are the very definition of potential: they have contained in their DNA, the potential to become virtually any cell in the body. Scientists have been working for decades to harness this power to use as medicine—think replacing damaged cells with brand new one—which could treat or even cure everything from diabetes to heart disease.

However, so-called regenerative medicine is still in its early days and very few stem cell therapies have been found to be effective. Part of the problem is scientists still don't fully understand how a stem cell transforms into its final form, be it a blood cell or heart cell—and without a clear understanding of that process, scientists can't control it to use as a therapy.

One of the lingering questions is how a cell's genes are expressed over time, from DNA to RNA to protein. The genome doesn't simply follow the instructions encoded in its DNA; it responds to signals from the environment that tell it what to express and when to express it, by making alterations to the structure of chromatin, the tightly wound bundle that contains the DNA. These chemical signals are called the epigenome.

Furthermore, for a gene to be expressed, its DNA must be transcribed into RNA. The read-out of a cell's RNA is called the transcriptome.

"The big question in the field is which changes first, the epigenome or the transcriptome," said Joshua Welch, Ph.D., an assistant professor in the Department of Computational Medicine and Bioinformatics at the U-M Medical School. A study from his team, published in Nature Biotechnology, provides a mathematical model that may be used to estimate this timing.

Our model can tell us which things are changing first–epigenome or gene expression--and how long it takes for the first to ramp up the second.
Joshua Welch, Ph.D.

Until recently, researchers could not see gene expression in an individual cell. Thanks to single cell sequencing techniques, they now can. But the timing of changes is still hard to visualize, as measuring the cell destroys it.

"To address this, we developed an approach based on models in basic physics," explained Welch, "treating the cells like they are masses moving through space and we are trying to estimate their velocity."

The model, dubbed MultiVelo, predicts the direction and speed of the molecular changes the cells are undergoing.

Like Podcasts? Add the Michigan Medicine News Break on Spotify, Apple Podcasts or anywhere you listen to podcasts.

"Our model can tell us which things are changing first–epigenome or gene expression--and how long it takes for the first to ramp up the second," said Welch.

They were able to verify the method using four types of stem cells from the brain, blood and skin, and identified two ways in which the epigenome and transcriptome can be out of sync. The technique provides an additional, and critical, layer of insight to so called cellular atlases, which are being developed using single cell sequencing to visualize the various cell types and gene expression in different body systems.

By understanding the timing, Welch noted, researchers are closer to steering the development of stem cells for use as therapeutics.

"One of the big problems in the field is the artificially differentiated cells created in the lab never quite make it to full replicas of their real-life counterparts," said Welch. "I think the biggest potential for this model is better understanding what are the epigenetic barriers to fully converting the cells into whatever target you want them to be."

Additional authors on this paper include Chen Li, Maria C. Virgilio, and Kathleen L. Collins.

Paper cited: "Single-cell multi-omic velocity infers dynamic and decoupled gene regulation," Nature Biotechnology. DOI: 10.1038/s41587-022-01476-y

Live your healthiest life: Get tips from top experts weekly. Subscribe to the Michigan Health blog newsletter

Headlines from the frontlines: The power of scientific discovery harnessed and delivered to your inbox every week. Subscribe to the Michigan Health Lab blog newsletter


More Articles About: Lab Report Basic Science and Laboratory Research Future Think Genetics All Research Topics
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of healthcare news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]

734-764-2220

Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Subscribe
Featured News & Stories Jianping Fu, Ph.D., Professor of Mechanical Engineering at the University of Michigan and the corresponding author of the paper being published at Nature discusses his team’s work in their lab with Jeyoon Bok, Ph.D. candidate at the Department of Mechanical Engineering.
Health Lab
Human stem cells coaxed to mimic the very early central nervous system
The first organized stem cell culture model that resembles all three sections of the embryonic brain and spinal cord could shed light on developmental brain diseases
Graphic showing pills, a heart and brain with data on aspirin use
Health Lab
Aspirin can prevent a second heart attack or stroke, but many don’t use it
Washington University School of Medicine and Michigan Medicine researchers found that fewer than half of people who have experienced a heart attack or stroke use aspirin to prevent a second one.
Illustration of a microscope
Health Lab
Hippo signaling pathway gives new insight into systemic sclerosis
Study focuses on Hippo signaling pathway as critical link between fibrosis, vascular dysfunction, and sex bias in systemic sclerosis
Headshot of Anne Draelos
Research News
U-M's Anne Draelos named a 2024 Sloan Research Fellow in neuroscience
Anne Draelos, Ph.D., Assistant Professor of Biomedical Engineering and Computational Medicine & Bioinformatics, has been named a 2024 Sloan Research Fellow in Neuroscience.
vial of blood in container lab blue yellow grainy graphic
Health Lab
Unveiling potential diagnostic, treatment target for APS-related thrombocytopenia
Researchers at the University of Michigan Health have unveiled a new mechanism that drives thrombocytopenia and a potential clinically actionable biomarker for antiphospholipid syndrome associated thrombocytopenia.
sketched out bacteria in a dish yellow and blue colors of U-M
Health Lab
Bacteria in the mouth linked to pulmonary fibrosis survival
Bacteria in the mouth may play a role in survival from idiopathic pulmonary fibrosis (IPF).