The signals that cause cells to destroy themselves

The signals that cause cells to destroy themselves

The signals that make cells self-destructing

CVM cells (red) follow along a track made of TVM (green) cells. The TVM cells emit a signal that lets the CVM cells know that they are going in the right direction. The CVM cells are approaching a bend in the embryo where they will encounter high BMP (blue) signals, which will indicate that the CVM needs to replicate itself and multiply. BMP signaling also triggers the expression of a “toxic” gene, called hid, and if the proliferating cells do not stay close to the TVM trace, hid will kill them. In this way, the developing embryo performs quality control, which ensures that all stubborn cells are eliminated. Credit: F. Macabenta

Most human hearts look almost identical – muscle cells in the same places, blood vessel structures in the same orientation. Organs such as hearts or stomachs look alike and function in the same way across individual organisms in a species because cells follow rigorous processes during evolution that take them exactly where they need to go.

The development process includes countless steps that must be done in an exact order and in a way. Studying these intricate steps is the focus of the laboratory of Caltech’s Angela Stathopoulos, professor of biology. The lab uses fruit flies, which have a 24-hour development cycle with significant changes that can be observed almost every minute, as a model system.

A new paper from the Stathopoulos laboratory examines caudal visceral mesoderm (CVM) cells, which will eventually become muscle fibers in the fruit fly’s gut. These cells migrate from the back of the developing embryo to the front over the course of six hours – the longest migration distance in the entire fruit fly embryogenesis.

New research identifies the mechanisms that ensure that all stubborn, migratory cells will self-destruct through a specific form of cell death called anoikis. Interestingly, resistance to anoikis is a precursor to many types of metastatic cancer. Understanding the pathways that guide healthy anoikis can ultimately provide insight into how cancers metastasize and why they invade certain parts of the body.

“Cell death is a normal, healthy part of development,” says Stathopoulos. “The migrating cell must constantly make decisions and find out if it is in the right place in the body. If it is not in the right place, it must destroy itself. We have now decided the ways by which the cell can do this.”

CVM cells (white) that migrate around a bend in the embryo. When they make this turn, they begin to multiply and multiply. Credit: F. Macabenta

The magazine is published online in the magazine Development cell on June 15. Frank Macabenta, senior research assistant in biology and biological technology at Caltech, is the study’s first author.

The CVM cells do not make their long journey through the fruit fly embryo alone. These 40 to 50 cells follow a kind of track that consists of another cell type called the trunk visceral mesoderm (TVM). TVM cells emit a chemical signal called a fibroblast growth factor (FGF), which lets a CVM cell know it is in the right place.

At the midpoint of their migration, the CVM cells must navigate around a sharp bend in the embryo, which is approximately U-shaped. At this point, CVM cells begin to multiply, waiting to be at the end of their journey soon, when it’s time to start building muscle. The problem is that as cells begin to multiply, some begin to slip away from the TVM track. Researchers have previously observed that this is the point where these lost cells will undergo anoikis and self-destruction.

A gene called hid (short for head involution defective) is responsible for anoikis. When hid is expressed in a cell, the cell will die. In the new work, Macabenta found that CVM cells begin to express hid when they make the turn around the curve in the embryo, but they do not die – unless they fall off the TVM track.

The team found that this is possible thanks to the FGF signals, which act as an antidote to hiding: If a cell falls off the track and therefore stops receiving FGF signals, it will die; it can stay alive even though hidden is expressed as long as it stays on track. In this way, the embryo can ensure that any stubborn cells are self-destructed while well-functioning cells are spared.

The signals that make cells self-destruct Graphic abstract. Credit: Development cell (2022). DOI: 10.1016 / j.devcel.2022.05.017

Finally, the team also discovered that a specific pathway, called bone morphogenetic protein pathway (BMP), controls the time at which cells begin to proliferate. BMP signaling is initiated just as the cells navigate in the U-shaped turn, approximately in the middle of their migration. It is this signal that allows cells to divide and grow in number.

Cells have an internal “clock”, known as the cell cycle, that controls the time of growth, DNA replication and cell division (mitosis). The team found that the time of hid expression is linked to the progression of the cell cycle, and when this is interrupted, hid is no longer expressed at the correct point during cell migration. BMP signaling is necessary for the cell cycle to be able to move forward myth and is therefore also necessary to time the exact expression of hid, since non-dividing cells cannot express hid in time to eliminate lost cells.

It is crucial that cells can have these programmed quality control mechanisms as stubborn cells can be detrimental to the proper development of the rest of the organism.

“When we removed the hid gene, the cells that came from the trace would survive and eventually invade and disrupt the central nervous system, where they really should not be,” says Macabenta. “They are not on the right track anymore, so they return to a kind of ‘Plan B’ where they find a place they have some affinity for. If you look at autopsies of people who have had metastases cancer, usually the metastatic cells will colonize specific sites. Our research works as a system to hopefully understand how this works, how cells go awry and find out the “next best” signals to follow. In future work we would like to see what other signals or signals CVM cells follows that lead them to the central nervous system. This may explain why certain types of metastases preferentially colonize other tissues. ”

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More information:
Frank Macabenta et al, BMP-controlled cell cycle progression drives anoikis during mesenchymal collective migration, Development cell (2022). DOI: 10.1016 / j.devcel.2022.05.017

Quote: The signals that make cells self-destructing (2022, June 15) retrieved June 15, 2022 from

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