New insights into the longevity of blood stem cells

Baylor College researchers identify cyclophilin A as key enzyme in hematopoietic stem cell longevity.

When it comes to the lifespan of our cells, not all human cells are created equal; while some cells only live for a couple of days, hematopoietic stem cells (HSCs) demonstrate remarkable longevity and regenerative capabilities. These blood-forming cells, which reside in the bone marrow, can activate to produce the myriad blood cells necessary for bodily functions, maintaining their functionality over an organism’s lifespan.

Now, recent research led by Baylor College of Medicine, published in Nature Cell Biology, has identified an enzyme as a crucial factor in maintaining the youthful and regenerative potential of HSCs [1].

Longevity.Technology: HSCs stand out for their ability to stay dormant yet retain the capacity to replenish blood cells continually (pretty important given that the human body makes about two million red blood cells every second). The Baylor team wanted to understand this phenomenon, and discover just how HSCs resist the aging process, and the answer appears to lie in cyclophilin A, an enzyme which is produced in large amounts in HSCs and which plays a key role in ensuring these cells retain their regenerative potential and avert the effects of aging.

“A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life,” said corresponding author Dr André Catic, assistant professor and CPRIT Scholar in Cancer Research in the Huffington Center on Aging at Baylor. “With age, proteins tend to misfold, aggregate and accumulate inside the cell, which leads to toxic stress that can disrupt cell function [2].”

Cells that undergo frequent division, such as progenitor cells, can dilute protein aggregates during cell division. HSCs, however, are long-lived and divide infrequently, and this means they face the challenge of managing misfolded proteins that could lead to toxic stress – despite this, they manage to remain resilient to aging.

“Understanding the molecular mechanisms that contribute to HSC aging not only contributes to the field of normal HSC biology, but also may have significant clinical relevance for cancer treatment,” said co-first author of the work, Dr Laure Maneix [2].

The busy chaperone

Earlier research has indicated that mammalian cells produce hundreds of molecular chaperones, which are proteins responsible for maintaining or altering the three-dimensional structure of other proteins. Among these, cyclophilins are particularly abundant and have been linked to the aging process; however, their specific impact on cellular proteins had not been investigated until now.

Cyclophilin A, also known as PPIA, emerged as a prominent chaperone in HSCs from the team’s characterization of the protein content in these cells. The research revealed that the levels of cyclophilin A significantly decrease in aged HSCs, and further experiments demonstrated that eliminating cyclophilin A in HSCs accelerated their aging, while reintroducing it restored their regenerative function, underscoring the enzyme’s pivotal role in HSC longevity.

Brought to order

The Baylor College study then focused on the mechanisms by which cyclophilin A operates, particularly looking at its interaction with intrinsically disordered proteins (IDPs). IDPs are proteins that lack a fixed three-dimensional structure, enabling them to interact flexibly with various cellular components. These interactions are crucial for regulating multiple cellular processes.

“We found that proteins enriched in intrinsically disordered regions are frequent targets of the chaperone,” Catic said.

“Due to their flexible nature, intrinsically disordered proteins are inherently prone to aggregation,” he added. “Cyclophilin A supports these proteins in fulfilling their functions and simultaneously prevents them from clumping [2].”

Cyclophilin A’s role involves stabilizing these intrinsically disordered proteins, ensuring their proper function and preventing the accumulation of misfolded proteins. The findings suggest that cyclophilin A binds to these proteins from the moment of their synthesis, playing a preventive role against cellular stress and degradation.

“As these proteins are being made, cyclophilin A makes sure they keep the appropriate conformations and are maintained at sufficient levels,” Catic said. “Genetic depletion of cyclophilin A results in stem cells distinctively lacking intrinsically disordered proteins [2].”

“For the first time, our study showed that producing disordered proteins and maintaining the structural diversity of the proteins in a cell plays a role in HSC aging,” Maneix said [2].

This research sheds light on the broader implications of molecular chaperones in cellular aging and longevity. The ability of cyclophilin A to maintain protein integrity in HSCs suggests potential therapeutic applications for enhancing stem cell function in aging or disease contexts, and by bolstering cyclophilin A levels, it might be possible to extend the regenerative capacity of HSCs, offering new avenues for treating age-related hematopoietic decline and related disorders.

The implications of this research extend beyond hematopoietic stem cells. Understanding how molecular chaperones like cyclophilin A contribute to cellular longevity could inform strategies to mitigate aging effects in other long-lived cell types. The role of chaperones in preserving protein function is a vital area of study, with potential applications in regenerative medicine and age-related disease treatment, and researching how cyclophilin A function could be harnessed therapeutically could potentially lead to innovative treatments that support healthy aging and combat degenerative diseases.

[1] https://www.nature.com/articles/s41556-024-01387-x
[2] https://blogs.bcm.edu/2024/04/30/from-the-labs-uncovering-the-secret-of-long-lived-stem-cells/