When thinking about red blood cells, the image of red, doughnut-dimpled discs whizzing through our blood vessel highways to deliver oxygen around the body comes to mind.
But did you know that out of the thousands of cell types, red blood cells are just one of three types which lose their nucleus – and the only one to push its nucleus out?
In this instalment of LIMS Explains, recently graduated LIMS PhD student Dr Lucas Newton and LIMS Director Professor Patrick Humbert break down this unique process.
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What is a cell nucleus?
The nucleus is the cell’s driver. Housed in a membrane, it contains all the genetic information for that cell. DNA replication, transcription and RNA processing all take place here so the cell fulfils its function.
Red blood cells are one of three types of cells in the human body to lack a nucleus – the other two are immature skin cells (epidermal keratinocytes) and lens fibre cells in the eye. But even within these three, red blood cells are unique. Both lens fibre cells and immature skin cells degrade their nucleus as they mature in a process called “denucleation”. Red blood cells, however, go through a different process called “enucleation”, whereby they push the nucleus out.
Why do red blood cells need a nucleus to develop?
All blood cells come from particular types of stem cells found in bone marrow called “hematopoietic stem cells”. While nearly all types of cells in the body, including white blood cells, need to keep their nucleus for ongoing DNA replication and transcription to ensure it functions as they should, red blood cells are special as they have just one job: To transport haemoglobin around the blood stream.
Haemoglobin is a protein which turns red when it binds with oxygen. It’s what gives blood its colour, and is how red blood cells carry the oxygen we breathe to tissues and organs throughout our bodies.
The nucleus’s job in a developing red blood cell is to instruct it to produce haemoglobin, which is made in the early stages of development. Once that’s done, they no longer need the nucleus to instruct them what to do as they only have one task to carry out.
Why do red blood cells lose their nucleus?
In the final stages of development, the red blood cells – called “erythroblast” at this stage – become packed with haemoglobin. The cell’s nucleus is quite large, so to ensure the maximum amount of oxygen possible is transported around the body our red blood cells have evolved to shed the nucleus, which makes room for even more haemoglobin. Getting rid of the nucleus also makes the cells more flexible, which helps them squeeze through the tiny capillaries and blood vessels in the body.
How does the nucleus leave the red blood cells – and what happens next?
As the red blood cells reach maturity, they begin the enucleation process - a resource-intensive and unique cellular event to push out the nucleus.
In this process, the cell’s growth and reproductive cycles stop and the structural components change to segment it into two daughter cells: a reticulocyte, which will enter the bloodstream and become the red blood cells we are familiar with, and a pyrenocyte, which contains the nucleus.
Once released, the pyrenocyte gives off “eat me” signals, and are then gobbled up by white blood cells to be broken down and recycled for other uses in the body.
What does the research tell us?
Red blood cell enucleation repurposes several genes, molecular pathways, and regulators of other cellular phenomena such as cell division (cytokinesis) and programmed cell death (apoptosis). This highlights how unique enucleation is, and opens ups interesting but unanswered questions about how mammals evolved to do this.
Understanding more about enucleation will also help with endeavours to produce red blood cells “ex vivo” - outside the body - for transfusion medicine. Currently, the enucleation process slows down production of ex vivo red blood cells, but if this issue can be solved it could transform the difficulties we have with blood supplies for transfusion.
Blood disorders such as Diamond Blackfan anaemia and myelodysplastic syndrome are also associated with enucleation issues. As such, better understanding of the process will open the door for the development of better treatments for these diseases.
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Recently, Dr Lucas Newton and Professor Patrick Humbert published a graphical review of a paper in Cell Science which examined how why this process occurs. Read the review at Cell Science.
