🧪 Rejuvenation: Scientists restore some properties of aged stem cells

What if we could rejuvenate the stem cells of our immune system?

In a collaborative study published in Cell Stem Cell, researchers have explored a promising lead. By targeting the "recycling centers" of our cells, the team managed to restore certain properties of aged murine stem cells. This breakthrough offers prospects for healthier aging and the development of treatments for blood cancers.

Aging of the Blood

Our bone marrow houses hematopoietic stem cells (HSCs), which can be considered the "mother cells" of blood. Their role is to constantly produce new red blood cells, which carry oxygen, platelets to stop bleeding, and white blood cells, which constitute our immune system.

With age, these mother cells age and deteriorate. They lose their ability to self-repair, leading to a weakened immune system and an increased risk of infections and blood diseases, including blood cancers.

A Discovery at the Heart of the Cellular "Recycling Center"

The researchers discovered that the key to this aging process lies in lysosomes. A lysosome can be considered the cell's degradation center, also functioning as a recycling and storage bin. It breaks down waste and transforms it into a new energy source.

Thanks to cutting-edge single-cell analysis technologies, which allow scientists to examine cell health one by one, and numerous functional approaches, the team discovered that in aged mice, these recycling units become too scarce and "out of control." They become excessively acidic and stop functioning correctly. This causes an accumulation of molecular "waste," triggering a state of constant inflammation. To ensure the reliability of these results, all underlying mechanisms were first established ex vivo before being successfully confirmed in vivo in mice.

Key findings of the study:
- Targeted Reversal: By using a specific inhibitor (vacuolar ATPase inhibitor) to mitigate lysosomal hyperactivation, the researchers managed to restore lysosomal integrity and stem cell function.
- 8-fold Increase in Efficacy: The ex vivo treatment of these aged stem cells with this inhibitor increased their ability to produce new blood cells once transplanted in vivo by more than eight times.
- Inflammation Suppression: The treatment reduced the activation of the cGAS-STING pathway, a major driver of chronic inflammation and stem cell aging, by helping the cell better process mitochondrial DNA waste.
Future Directions

These results offer a promising roadmap for therapeutic strategies aimed at:
- Reversing age-related blood disorders.
- Improving outcomes of bone marrow transplants in elderly patients.
- Optimizing gene therapy protocols relying on healthy and robust stem cells.

This project highlights the success of a strategic partnership initiated in 2023, when Professor Saghi Ghaffari joined Mickaël Ménager's laboratory at the Imagine Institute on a sabbatical leave. This collaboration combined two areas of expertise: Mount Sinai's in stem cell biology, and the Imagine Institute's in single-cell genomics and computational biology.

"By combining our expertise in technologies that allow us to work at the single-cell level with a deep biological understanding of stem cell aging, we improved the ability of stem cells to self-renew and produce immune cells in aged individuals to a level comparable to stem cells from young individuals," says Mickaël Ménager, head of the SCInflaNet laboratory: Single-cell inflammatory responses and multi-OMICs networks at the Imagine Institute and Inserm Research Director.