Dr. Stephanie Cherqui has previously shown that if you transplant hematopoietic stem cells (HSCs) into cystinosis mice, you get stem cell engraftment with reduction in cystine in the tissues and preservation of organ function. She is currently working on safety studies so that we can move forward with human trials with autologous HSC transplant for patients with cystinosis.
But how do the stem cells actually fix the cystinosis cells? Dr. Cherqui and her lab recently published a paper in Stem Cells revealing the mechanism. Several hypotheses had been suggested. Do the stem cells turn into new kidney cells, or do they fuse with the diseased cells to create a functioning hybrid? It turns out it’s neither.
First you have to remember that cystinosis is a disease of the lysosome. The lysosome is like the recycling plant of the cell. It takes up old proteins, digests them into amino acid building blocks, and spits them out through transporter pumps to be reused.
Cystinosin is the transporter that pumps out cystine, and if it is broken, like it is in cystinosis, then the cystine can’t get out of the lysosome. Cystine builds up, damaging the lysosome and the cell. Cystinosin is probably involved in a lot of other cellular functions too, which explains why giving people cysteamine doesn’t cure cystinosis. You can’t just get rid of cystine; you have to replace the Cystinosin transporter somehow.
Dr. Cherqui showed that most of the stem cells turn into macrophages after transplantation. Macrophages are a type of immune cell, and their name literally means “big eater.” Macrophages like to munch on bacteria, and they also clean up the big mess made by the other immune cells that are fighting viruses and bacteria. Since the macrophage is designed to clean up, it has lots of LYSOSOMES!
Dr. Cherqui’s latest research shows that these helpful macrophages respond to a distress call from the sick cystinosis cells by creating little tubes, called tunneling nanotubules (TNTs), through which they share lysosomes with the sick cells. Healthy lysosomes with the Cystinosin transporter move into the cystinosis cells, and the sick lysosomes move out of the cystinosis cells and into the macrophages. It’s almost like a lysosome transplant!
In the movie below, posted with Dr. Cherqui's paper in Stem Cells, you can actually see the lysosomes (the little green dots) leaving the macrophage through the tunneling nanotubules to the cystinosis cells, which are red. So cool!
This research could have big implications for other diseases. Cystinosis is just one of fifty lysosome disorders. Other lysosome disorders include Tay-Sachs disease, Fabry disease, Niemann-Pick disease, Gaucher disease and metachromatic leukodystrophy. What if HSC transplantation could swap out the broken lysosomes in these diseases? It's also interesting to note that lysosomes aren't the only organelles that move across the tunneling nanotubules. Dr. Cherqui and other researchers have also noted mitochondria making the trek. Mitochondria are the "powerhouse" of the cell, where most of the energy required for cellular function is generated. There are many mitochondrial disorders, and it is possible that HSC transplantation could be used to treat these as well. The cure for cystinosis could be the cure for a whole host of genetic diseases!