Stem-cell-controlled destruction of misfolded proteins declines with age

The specific pathway that blood stem cells use to degrade proteins to keep themselves clean and healthy has been discovered, and that this process becomes disrupted with age.

Hematopoietic stem cells (HSCs), or blood stem cells, are a type of immature cell that can develop into any type of blood cell and regenerate these cells throughout life. To stay fit and healthy, HSCs must maintain a tight balance between protein synthesis, transportation to specific locations within the cell, and degradation, also known as proteostasis. When proteostasis is disrupted and misfolded proteins start to accumulate, this impairs stem cells' ability to self-renew and has been associated with cancer and age-related disorders.

'Stem cells are in it for the long haul,' said senior study author Dr Robert Signer, from the University of California San Diego School of Medicine. 'Their need for longevity requires them to be wired differently than all the short-lived cells in the body.'

Dr Singer and his colleagues published results of a study in Cell Stem Cell, detailing the process through which HSCs remove misfolded proteins. Most cells primarily use the proteasome system to degrade misfolded proteins, whereby individual misfolded proteins are tagged and broken down by mobile enzymes called proteases. Unexpectedly, the researchers observed that HSCs primarily rely on a different pathway. Instead, HSCs collect misfolded proteins and form a collection of aggregated proteins, known as aggresomes. They are then all broken-down together by enzymes called lysosomes in a process called aggrephagy, which degrades and recycles cellular components.

'What's very unusual here is this pathway was thought to only be triggered as an extreme stress response, but it's actually the normal physiological pathway that's used by stem cells,' said Dr Signer. 'This emphasises how critical it is for stem cells to prevent stress so they can preserve their health and longevity.'

To demonstrate the importance of aggrephagy in HSCs maintaining proteostasis, the scientists genetically disabled autophagy, and found that HSCs started to accumulate misfolded proteins and have impaired function. This also happened when they only genetically deleted BAG3, a protein which promotes the movement of proteins to aggresomes. These dysfunctional changes in HSCs resembled changes known to occur in HSCs during ageing, which led the researchers to examine aggresomes in old adult HSCs, and discovered that while most young adult HSCs contained aggresomes, old adult HSCs almost completely lacked aggresomes.

Thus, the scientists concluded that aggresomes and the aggrephagy pathway are critical for young adult HSCs to preserve proteostasis and health, but that these processes become dysregulated during ageing.

'Our hope is that if we can improve stem cells' ability to maintain the aggrephagy pathway, we will preserve better stem cell fitness during ageing and mitigate blood and immune disorders,' said Dr Signer.