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Signals from dying cells are necessary for stem cell differentiation

Headshots of (L-R) Loic Fort sitting in front a mirror attached to a red wall; Ian Macara, wearing a coat and tie; Vivian Gama wearing a floral top.
L-R: Loic Fort, Ian Macara, Vivian Gama

By Emily Overway

A Vanderbilt laboratory is investigating the sequence of events necessary for the differentiation of stem cells into heart cells—a key step in embryonic development. Postdoctoral fellow Loic Fort and Louise B. McGavock Professor and Chair of Cell and Developmental Biology Ian Macara published their most recent discoveries on this topic in Nature Cell Biology. Associate Professor of Cell and Developmental Biology Vivian Gama is a collaborator on the study.

We sat down with Fort to learn more about their work.

What issue/problem does your research address?

Human embryonic stem cells growing in a dish can change into any of the cell types found in the body (liver, skin, brain, etc.). During development, WNT signaling is crucial for the formation of the heart; in a dish in the laboratory, the transition from stem cells to heart cells can be artificially stimulated using a chemical. Yet, surprisingly little is known about the cell biology of human stem cells and the changes that occur after the transition into heart cells begins. Our research sought to better understand these early steps in this conversion.

What was unique about your approach to the research?

We performed careful microscopic analysis of embryonic stem cell cultures and made movies of the cells as they began to change into heart cells. By visualizing the cells continuously during this crucial period of differentiation, we discovered that many of the cells initially die and that the survivors then change their shape and behavior.

What were your findings?

We found that if we prevented the stem cells from dying, adding the chemical signal that artificially stimulates WNT signaling no longer induced the conversion of stem cells to heart cells. Upon further investigation, we found that the dying cells released a small molecule that was necessary for the living cells to respond to the chemical signal. In short, we discovered that two separate cues—one from the added chemical and one from surrounding dying cells—are required for embryonic stem cells to become heart cells.

What are the benefits of this research in the short and long terms?

In the short term, this project will improve our understanding of the sequence of events necessary for the generation of heart cells from embryonic stem cells, adding to our basic knowledge of early human development. In the long term, we hope that this work will help us to understand a variety of heart defects.

Where is this research taking you next?

Our next steps will be determining if stem cells in an organism behave the same as those in a dish. To do this, we are creating gastruloids—3D aggregates of embryonic stem cells—that recapitulate early events of development. Additionally, we plan to determine what is happening inside the cells as they respond to the stimuli of ATP, an energy-providing molecule, and WNT signaling and why these stimuli specifically inform stem cells to differentiate into heart cells.


This work was funded by the National Institute of General Medicine and the National Cancer Institute.

Go further

The paper “Stem cell conversion to the cardiac lineage requires nucleotide signalling from apoptosing cells” was published in Nature Cell Biology in April 2022.