Researchers have found that cyclophilin A, an enzyme found in large quantities in hematopoietic stem cells, plays a crucial role in maintaining the regenerative potential of these cells and preventing aging through an unexpected mechanism. Nothing lives forever, but compared to other cells in the body, hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs are blood-forming cells — they give rise to rapidly dividing progenitor cells, which in turn generate hundreds of billions of cells to fulfill the daily demand of oxygen-delivering red blood cells, disease-fighting white blood cells and clo rnrn
Hematopoietic stem cells (HSCs) are usually inactive in the bone marrow but have the capacity to constantly refresh and renew blood cells, maintaining a relatively youthful state throughout an organism’s life. Researchers at Baylor College of Medicine discovered that the key to the longevity of HSCs and their ability to resist the effects of aging lies in the enzyme cyclophilin A, which is abundantly produced in these cells, according to a study published in Nature Cell Biology.
Stem cells live on!
“The build-up of proteins that have reached the end of their lifespan is a key factor in cellular aging,” explained Dr. André Catic, the lead author of the study and assistant professor at Baylor’s Huffington Center on Aging. “As cells age, proteins tend to fold incorrectly, clump together, and accumulate within the cell, causing harmful stress that can interfere with normal cell function.”
Cells that divide frequently, such as progenitor cells, can get rid of protein build-up through dilution. However, long-lasting HSCs, which don’t divide often, face the challenge of dealing with the accumulation of misfolded proteins.Aging can cause cells to accumulate damaged proteins and experience toxic stress, but hematopoietic stem cells (HSCs) are not affected by aging. Scientists are trying to understand how this happens in order to gain insight into normal HSC biology and potentially improve cancer treatment. Dr. Lauren Maneix, a co-first author of the research, emphasized the importance of understanding the molecular mechanisms behind HSC aging. One key factor that has been identified is the presence of molecular chaperones, which are proteins that help maintain or alter the three-dimensional structure of other proteins in mammalian cells.The aging process has been linked to the presence of cyclophilins, a type of chaperone protein. However, the specific impact of these proteins on cellular proteins had not been previously explored. The researchers conducted experiments with mice to study the protein content of HSCs and found that cyclophilin A is a prevalent chaperone in these cells. They also observed that the expression of cyclophilin A decreased significantly in aged HSCs. Furthermore, they found that genetically eliminating cyclophilin A accelerated the natural aging process in the stem cell compartment. On the other hand, reintroducing cyclophilin A into aged HSCs enhanced the aging process.The study found that cyclophilin A is crucial for the long-term survival of hematopoietic stem cells (HSCs). The researchers also discovered that cyclophilin A interacts with proteins that are rich in intrinsically disordered regions, helping to maintain their stability. Intrinsically disordered proteins have the ability to change their shape in order to interact with other molecules, making them important for various cellular processes. These findings shed light on the intricate relationship between cyclophilin A, intrinsically disordered proteins, and the longevity of HSCs.Proteins play a crucial role in cellular processes by facilitating specific interactions between molecules. According to Catic, intrinsically disordered proteins are prone to aggregation due to their flexible nature. Cyclophilin A helps these proteins carry out their functions and prevents them from clumping together.
Additionally, the research indicates that cyclophilin A interacts with intrinsically disordered proteins as soon as they are synthesized. Catic explained that cyclophilin A ensures these proteins maintain the correct conformations and are present in adequate levels as they are being produced. Depleting cyclophilin A genetically, A study has found that stem cells lack disordered proteins, which is important for aging. This is the first study to show that the production of disordered proteins and maintaining protein structural diversity in a cell plays a role in stem cell aging,” said Maneix. Co-first author Polina Iakova, along with several other individuals, also contributed to this study.
