Cell Stem Cell: Targets CD47, which not only treats cancer, but also restores muscle strength and fights aging

CD47, a transmembrane protein encoded by the CD47 gene in the human body, belongs to the immunoglobulin superfamily
.
Since the 80s of the 20th century, CD47 has been found to be highly expressed
in a variety of human hematological tumors and some solid tumors such as bladder cancer and brain tumors.

In 2009, Professor Irving Weissman, a well-known cancer stem cell expert at Stanford University School of Medicine, published a paper in Cell showing that tumor cells highly express CD47, which releases "Don't eat me" signals by binding to signal regulatory protein α (SIRPα) on the surface of macrophages, thereby preventing tumor cells from being engulfed
by macrophages.
Since then, CD47 has become a new generation of popular cancer treatment targets
.

A new study by Stanford University School of Medicine shows that in addition to CD47 being used by cancer cells as a "don't eat me" signal, aging muscle stem cells may also use this method to avoid being eliminated
by the immune system.
After receiving antibody therapy targeting the CD47 pathway, the old mice regained their youthful muscle strength
.

On November 15, 2022, researchers at Stanford University School of Medicine published a report in Cell Stem Cell titled Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration Research papers
.

The study utilized single-cell mass spectrometry flow cytometry to identify high CD47 expression as a hallmark of dysfunctional muscle stem cells, and further determined that platelet-reactive protein-1 (THBS1) binds to CD47 on the surface of muscle stem cells, thereby inhibiting muscle stem cell activity
.
Blocking the binding of THBS1 to CD47 by antibodies can promote muscle development and regeneration
in elderly mice.

This study has important clinical implications, suggesting that we may be able to target CD47 to promote muscle recovery after surgery, as well as to prevent muscle strength loss
due to aging or long-term inactivity.

It is well known that as we age, muscle stem cells lose their ability to
divide rapidly due to injury or lack of exercise.
But it's unclear why, and it's difficult to isolate the different subpopulations of these cells for study
.

In this latest study, the team used single-cell mass spectrometry flow cytometry to identify subsets of mouse muscle stem cells whose cell surface markers change
relative proportionally with age.
Through this technique, the research team quickly discovered that there was one molecule that stood out - CD47
.
CD47 is highly expressed on some muscle stem cell surfaces and low on
others.
They further found that among muscle stem cells from aged mice, muscle stem cells with high CD47 expression predominated, while muscle stem cells with low CD47 expression dominated in young mice
.

Dr.
Ermelinda Porpiglia, first author and co-corresponding author of the paper, said the finding was somewhat unexpected because CD47 has previously been used as an immunomodulator in cancer immunotherapy research
.
But the latest finding makes sense — like cancer cells, senescent stem cells may use CD47's "don't eat me" signal to escape immune system clearance
.

The research team found that high levels of CD47 on the surface of muscle stem cells correlated with
a decline in their function.
When high-expression muscle stem cells were transplanted into the leg muscles of other mice, the muscle stem cells were less likely to colonize or form new muscles
.

Further studies found that platelet-reactive protein-1 (Thrombospondin, THBS1) binds to CD47 on the surface of muscle stem cells, inhibiting the activity
of muscle stem cells.
The THBS1 protein accumulates in skeletal muscle and cardiac muscle with age, and the expression of THBS1 protein in skeletal muscle after exercise decreases
.

Next, the research team developed antibodies that recognized the THBS1 protein and blocked its binding to CD47, adding this antibody to aged mouse muscle stem cells cultured in vitro, which divided more vigorously; This antibody is injected into the leg muscles of elderly mice, which develop larger and stronger
.
In addition, the injection of the antibody can also help injured old mice recover as quickly as young mice and regain strong muscles
.

The antibody was indeed ineffective in mice with CD47, suggesting that the interaction between THBS1 protein and CD47 is essential for muscle stem cell activity and is an important regulatory signal
for aging and damage repair.

The research team said that anti-THBS1 protein antibody therapy is a method of local and temporary activation of muscle stem cells in elderly mice, and it is hoped that in the future, this antibody can be injected in specific parts of the body to help the elderly regenerate muscles, or to treat muscle loss
caused by disease or surgery.

In addition, the research team plans to investigate whether anti-CD47 antibodies stimulate the immune system to remove aging, dysfunctional muscle stem cells
.

Finally, the corresponding author of the paper said that whether cancer immunotherapy targeting CD47 can also block the TSP protein pathway is of great research value, and if possible, anti-CD47 antibodies are expected to be used to treat cachexia that causes muscle loss (extreme wasting, anemia, weakness), which is common
in cancer patients.

Original source:

Ermelinda Porpiglia， et al.
Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration.
Cell Stem Cel， 2022.