Aging support cells weaken beneficial signals to stem cells and sustain inflammation: a model presented in an Aging Cell review

Aging support cells weaken beneficial signals to stem cells and sustain inflammation: a model presented in an Aging Cell review

On October 28, researchers at Simon Fraser University published a review of studies on bone marrow, lungs, muscle and other tissues. The authors compared experiments in which stem cells were grown with young or old support cells with attempts to improve tissue repair by changing the signals exchanged between cells.

Stem cells receive signals from surrounding cells that tell them when to remain in reserve and when to divide and repair tissue. This local environment is called the niche. Its support cells include mesenchymal stromal cells (MSC). They release chemokines, signaling proteins that regulate cell movement and interactions, including the recruitment of immune cells to sites of injury.

DNA damage, metabolic disturbances and inflammation can cause some MSC to enter senescence: the cells remain alive, stop dividing and change the mix of substances they release. The authors describe the role of senescence as follows:

“MSC senescence is both a consequence of molecular aging and an amplifier of subsequent stem cell dysfunction.”

In this model, the signals that retain stem cells in the niche and regulate their division become weaker. MSC themselves become less responsive to signals from neighboring cells. Brief recruitment of immune cells helps repair tissue after injury. Aging MSC continue to release substances that attract immune cells, sustaining inflammation. The inflammatory environment promotes further cellular senescence, making the disruption of signaling persist.

To distinguish the effects of stem cell age from those of support cell age, researchers in a 2021 experiment collected two types of lung cells from young and old mice. They paired epithelial cells capable of renewing the lining of the lung’s air sacs with MSC in all four combinations and grew organoids, three-dimensional cellular models of these air sacs. Old epithelial cells paired with young MSC formed relatively normal hollow structures. Young epithelial cells paired with old MSC produced smaller, denser organoids.

A different observation prompted a 2020 experiment involving dental pulp, the soft tissue inside a tooth. Pulp cells selected for transplantation from young and old dogs differed little when grown in the laboratory, yet less tissue regenerated after transplantation into old teeth. The authors proposed that chronic inflammation in the cells’ surroundings was impairing regeneration. They chose to target CCR3, a receptor through which cells receive signals from CCL11, a chemokine associated with pulp inflammation. In dogs aged 5–6 years, they combined pulp cell transplantation with a blocker of this receptor. After 60 days, more pulp had regenerated and nerve fibers had grown more extensively than after the same transplantation without the blocker. In young dogs, the amount of regenerated pulp did not differ significantly with or without the blocker.

The review’s authors propose choosing an intervention according to what has gone wrong in the niche: replacing missing beneficial signals, blocking signals that sustain inflammation, or restoring the function of the support cells themselves.