The transition from reticulocytes to fully functional red blood cells has long been considered a brief stage, but new findings show that this process continues for at least a week, accompanied by intricate changes in cell membrane lipids and proteins. Understanding this late phase of development is not only fundamental for cell biology but may also inform the creation of transfusion-ready cells grown in the laboratory.

Professor Giampaolo Minetti of the University of Pavia; Dr. Isabel Dorn and Dr. Harald Köfeler of the Medical University of Graz; Dr. Cesare Perotti of the Fondazione IRCCS Policlinico San Matteo; and Professor Lars Kaestner of Saarland University collaborated on this study, published in Cell Death Discovery. Together they isolated two distinct populations of circulating human reticulocytes, as well as three age-defined erythrocyte groups, and analyzed how their lipid and protein compositions evolve over time.

The researchers showed that reticulocytes, though already disc-shaped and morphologically similar to mature red blood cells, undergo continuous remodeling. Levels of sphingomyelin and cholesterol rise, while phosphatidylcholine and phosphatidylserine decline, reflecting selective retention and removal of different lipid classes. As Dr. Minetti explained, “Reticulocytes and erythrocytes cannot perform de novo phospholipid synthesis, lipid remodeling likely requires selective removal from the membrane or exchange with plasma, possibly with the involvement of lipid transfer proteins such as VPS13A.”

Alongside lipid remodeling, the team observed a progressive loss of key structural proteins such as Band 3 and spectrin. Despite this, cells preserved their biconcave form while reducing their surface area by roughly ten percent as they matured. VPS13A, a protein known to shuttle lipids between membranes, remained detectable throughout much of the process, supporting its role in coordinating membrane adjustments.

One of the most significant outcomes is the reframing of the maturation timeline. Traditionally thought to conclude within one to two days after reticulocytes enter the bloodstream, the data now indicate that membrane composition continues to evolve for at least seven days. The inversion of certain lipid ratios — such as specific phosphatidylcholine subclasses — marks a clear boundary between reticulocytes and truly mature erythrocytes. As Dr. Minetti emphasized, “The timing for development of a mature red blood cell should be extended from the conventional one to two days in circulation, to at least one week, as judged from lipid composition.”

By combining precise cell sorting with lipidomic and protein analysis, the study highlights how red blood cells adjust their surfaces gradually, balancing the removal of some lipids with the selective enrichment of others. These results clarify a stage of human biology that had remained largely obscure and provide a more complete framework for future investigations.

Beyond its immediate impact on hematology, the work may aid the production of cultured red blood cells for transfusion by identifying lipid compositions that ensure long-term stability in circulation. It also opens questions about how proteins like VPS13A coordinate lipid trafficking in anucleate cells, a problem with broader implications for membrane biology.

Journal Reference

Minetti G., Dorn I., Köfeler H., Perotti C., Kaestner L. “Insights from lipidomics into the terminal maturation of circulating human reticulocytes.” Cell Death Discovery, 2025;11:79. DOI: https://doi.org/10.1038/s41420-025-02318-x