Nothing lives forever, but compared to other cells in the body, hematopoietic stem cells (HSCs) are significantly longer-lived. HSCs are hematopoietic cells. HSCs generate rapidly dividing progenitor cells that produce hundreds of billions of cells to meet daily demands for oxygen-carrying red blood cells, disease-fighting white blood cells, and blood clot-forming platelets. .
Although HSCs are normally dormant within the bone marrow, they have the ability to continuously activate and replenish blood cells, maintaining a relatively youthful profile throughout the life of the organism. What’s the secret to allowing HSCs to live longer and avoid the effects of aging? A team led by researchers at Baylor College of Medicine has discovered that the enzyme cyclophilin A, which is produced in large quantities within HSCs, maintains these cells’ ability to regenerate. , revealed in the journal Nature Cell Biology that this is the key to avoiding the effects of aging.
Long live stem cells!
“The driving force behind cellular aging is the accumulation of proteins that have reached the end of their useful life,” said corresponding author Andre Katic, Ph.D., assistant professor at Baylor’s Huffington Center on Aging and a CPRIT fellow in cancer research. “As we age, proteins tend to misfold, aggregate, and accumulate within cells, leading to toxic stress that can disrupt cellular function.”
Cells that undergo frequent cell division, such as progenitor cells, can handle protein aggregates by dilution. On the other hand, long-lived HSCs do not divide frequently and therefore face the problem of misfolded protein accumulation and subsequent toxic stress. Nevertheless, HSCs remain unaffected by aging. How are you doing?
“Understanding the molecular mechanisms that contribute to HSC aging will not only contribute to the field of normal HSC biology, but may also have significant clinical relevance for cancer therapy,” the study said. said Lauren Mannex, Ph.D., co-lead author. While working on this project, I joined the Catic lab.
Function of molecular chaperones
Previous studies have shown that mammalian cells express hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilin, one of the most abundant chaperones, is thought to be involved in the aging process. However, how they affect cellular proteins has not been studied until now.
Using mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a common chaperone. Further experiments showed that cyclophilin A expression was significantly reduced in aged HSCs and genetically removing cyclophilin A promoted natural aging of the stem cell compartment. In contrast, reintroducing cyclophilin A to aged HSCs enhanced their function. Taken together, these findings support that cyclophilin A is an important factor in the longevity of her HSCs.
Cyclophilin A, linking an intrinsically disordered protein to HSC lifespan
The researchers then investigated the proteins with which cyclophilin A interacts while maintaining its stability. “We found that proteins enriched in intrinsically disordered regions are frequent targets of chaperones,” Catic said.
Intrinsically disordered proteins naturally change their 3D conformation to interact with different proteins, nucleic acids, or other molecules. As a result, proteins rich in intrinsically disordered regions control many cellular processes by promoting specific activities between molecules. “Intrinsically disordered proteins are inherently prone to aggregation due to their flexible nature. Cyclophilin A supports these proteins to perform their functions while preventing aggregation,” he said. Catic said.
Furthermore, this finding suggests that cyclophilin A interacts with an intrinsically disordered protein from the moment of synthesis. “As these proteins are made, cyclophilin A ensures that they are kept in the proper conformation and at sufficient levels,” Catic said. “Genetic depletion of cyclophilin A results in stem cells that clearly lack the intrinsically disordered protein.”
“Our study shows for the first time that producing disordered proteins within cells and maintaining protein structural diversity plays a role in HSC aging,” Maneix said. .
Co-first authors Polina Iakova, Charles G. Lee, Shannon E. Moree, Xuan Lu, Gandhar K. Datar, Cedric T. Hill, Eric Spooner, Jordon CK King, David B. Sykes, Borja Saez, Bruno Di Stefano, Xi Chen , Daniela S. Krause, Ergun Sahin, Francis TF Tsai, Margaret A. Goodell, Bradford C. Berk, and David T. Scadden also contributed to this research.
