The stem cells that generate connective tissue may be therapeutic targets for various diseases

Disease and treatment 9. nov 2021 3 min Clinical Professor, Professor Niels Jessen, Assistant Professor Jean Farup Written by Kristian Sjøgren

Researchers have identified a type of cell in skeletal muscle that turns into adipose or connective tissue among people with type 2 diabetes. These cells may hold the key to treating various diseases with both well-known diabetes drugs and novel types of drugs.

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Muscles are not just muscles. They comprise many different cells with different roles.

There are muscle cells, stem cells that create muscle cells, endothelial cells, fat cells and the stem cells called the fibro-adipogenic progenitors that generate connective tissue and adipocytes.

However, the ratios between the cell types vary between people who are sick and healthy.

For example, a biopsy from the muscles of people with type 2 diabetes often contains large amounts of fat and connective tissue that is not present in muscle from healthy people.

This underpins a new study in which researchers also identified the types of stem cells that generate fat and connective tissue. These may eventually be potential therapeutic targets for diabetes, heart failure and other diseases.

“When people live with diabetes for years, their organs get filled with fat and connective tissue. Our discovery of the cells that differentiate into fat and connective tissue in the skeletal muscles is therefore important, since these cells can become a therapeutic target for people with diabetes as well as people with heart failure, in which connective tissue accumulates in the heart,” explains Jean Farup, Assistant Professor, Steno Diabetes Center Aarhus.

The research has been published in Cell Metabolism.

Mapped the genetics of skeletal muscle

Jean Farup and colleagues investigated what makes muscle tissue unhealthy among people with diabetes.

The researchers examined biopsies using RNA sequencing to determine the overall genetic expression of skeletal muscle among people with type 2 diabetes versus healthy controls. The results showed a major difference.

“The fact that people with type 2 diabetes have elevated expression of many of the genes associated with connective tissue formation in their skeletal muscles was a real eye-opener. We envisioned an altered expression of genes related to metabolism, but the expression was overwhelmingly related to the generation of connective tissue,” says Jean Farup.

Cell subgroups cause disorder in the muscles

The researchers then sought to identify the specific cells that overexpress the genes that generate connective tissue.

By examining the gene expression of individual cells at the single-cell level, they discovered that one type of cell overexpresses genes associated with generating connective tissue among people with type 2 diabetes.

These stem cells are called fibro-adipogenic progenitors, meaning that they have the potential to differentiate into both fat cells and connective tissue cells, which is unique to this cell type in skeletal muscle. They can also enter the cell cycle in which they eventually divide and grow in number and thereby accumulate in the muscle.

Finally, the researchers identified a subgroup of fibro-adipogenic progenitor cells (CD90+) that cause people with type 2 diabetes to accumulate fat and connective tissue in their muscles.

“People with type 2 diabetes have a selective increase in the CD90+ cells, which have a strong ability to divide and produce connective tissue proteins. It is also interesting that we may be able to target these cells for treatment and reduce the inappropriate generation of adipose and connective tissue without affecting the other cells,” explains Jean Farup.

Metformin inhibits inappropriate cells

The clinical perspectives of the new discovery may be substantial since the skeletal muscles are not the only organ to generate inappropriate connective tissue. This happens in the injured heart, but also other key organs such as kidney and liver display accumulation of connective tissue and fat, which may eventually lead to organ failure.

Inhibiting the ability of the CD90+ cells to divide, not only in the skeletal muscle but also in other organs, may thus have great therapeutic potential in many diseases.

The researchers therefore examined whether the generation of fat and connective tissue in the skeletal muscles differed among people with diabetes depending on the treatment they were receiving.

The people treated with metformin had reduced accumulation of the fibro-adipogenic progenitor cells in their muscles.

“This shows that this diabetes drug does more than just lower blood glucose. Many new drugs are being developed for diabetes, and optimizing the use of the various drugs requires knowing their mechanisms of action in detail,” says another researcher behind the study, Niels Jessen, Head of Research at Steno Diabetes Center Aarhus.

The reason metformin protects the heart

Jean Farup elaborates that the results indicate that metformin may be able to inhibit the degeneration of the skeletal muscles, and if it can do the same in the heart, it will probably be able to be aid the treatment of heart failure, in which excessive connective tissue is generated.

Experiments have also shown that people with heart failure seem to recover better if they are being treated with metformin for diabetes.

“We suspect that these effects are related to inhibition of the cells we have identified, which indicates that taking people with diabetes off metformin may have negative effects. Some evidence indicates that metformin has many other positive effects than improving blood glucose control,” concludes Jean Farup.

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