A lipid bilayer, called the plasma membrane, surrounds every cell. This protects the cell from the environment and keeps the insides in. Keeping material contained is important for many aspects of biology. Lipid bilayers form organelles and vesicles within the cell to contain specialized components. For example, powerful enzymes recycle old material in the cell. If not contained these enzymes would wreak havoc. To prevent this lysosomes contain the enzymes, protecting the cellular contents. Material from all over the cell can get added to lysosomes.
Vesicles move material from one place to another. Endosomes move material from the plasma membrane. Endosomes either fuze with lysosomes or recycle back to the plasma membrane. The lipid bilayer of an endosome will join with the plasma membrane. The contents of the endosome exit the cell. The endosome can contain even smaller vesicles. Outside the cell we call these vesicles exosomes.
During my PhD I discovered that exosomes can transfer proteins between kidney cells. Wilna Oosthuyzen continued this work by asking what regulates this process. She discovered that vasopressin regulates exosome uptake in collecting duct cells of the kidney.
It is very gratifying when a study builds on work I published earlier, and particularly when executed so well. I was very pleased to be able to contribute.
In an earlier post (TLR4) I discussed the TLR4 receptor. This receptor detects microbes and starts an inflammatory response. TLR4 is not the only receptor that detects microbes. There are many receptors the immune system uses. This redundancy prevents microbes going undetected and matches the response to the microbe. At least, when everything works. An excessive response can cause sepsis. In sepsis the response is so strong that it damages tissues and can even cause organ failure.
I have recently collaborated with Oliver Voss and John Coligan from the National Institute of Allergy and Infectious Diseases. They were studying CD300b. This is another receptor that binds lipopolysaccharides (LPS) like TLR4. CD300b then binds to TLR4 and enhances its signaling. This enhanced signaling can then cause more tissue damage, leading to sepsis.
Inhibiting TLR4 does not work well for treating sepsis in humans. This might be because some TLR4 signaling helps combat infecting microbes. Inhibiting CD300b might strike a healthy balance between continuing to fight the infection and the excessive signaling causing tissue injury.
Lipids are very important molecules in the human body. Different types of lipids include fats and some vitamins. Lipids form the membranes in and around cells, store energy, and signal between cells. Lipids, like fats and oils, do not dissolve in water. To get them around the body they form complexes with proteins. These complexes include LDL and HDL.
Your doctor may have requested blood tests for these. They are important in cardiovascular disease. To get lipids into cells receptors must bind the lipoprotein complexes. Sometimes rather than supporting the cell, lipid uptake can cause stress and inflammation. This is why doctors often check the levels of LDL and HDL.
CD36 is a receptor for lipoproteins. We investigated the role of CD36 in chronic kidney disease (CKD). Breaking this receptor by changing the DNA that creates it protected against CKD. Similar protection happened with a small peptide inhibitor. This is important because it is easier to help patients by giving them a drug than by trying to change their DNA.
There are several receptors that detect microbial products. They are responsible for triggering an inflammatory response by the innate immune system. This is important to guard against infections. Sometimes inflammation can happen when it is not needed to protect against infection. A low level of inflammation is sometimes detected in chronic diseases.
Toll-like receptor 4 (TLR4) detects lipopolysaccharides (LPS). The outer layer of gram-negative bacteria contains LPS. TLR4 might also detect some molecules released during tissue damage. We investigated the role of TLR4 in chronic kidney disease (CKD).
Breaking TLR4 so it could not trigger the innate immune system protected against CKD.
Many diseases are very complex, involving many biological pathways. It is very difficult to find a single drug with actions on enough pathways to slow or reverse many diseases. As an alternative there is excitement around using cells to treat disease. Cells can sense their environment and change their response to match.
Mesenchymal stem cells (MSCs) have performed well in many types of disease. I currently work in the Renal Diagnostics and Therapeutics Unit at NIDDK. Before I joined the group they found MSCs were beneficial in sepsis. Treatment had to be soon after injury limiting the clinical usefulness. One potential reason for this was most MSCs got stuck in the lungs. If more cells got to the kidneys they might work better. At the time it was not known how to guide more cells to the kidneys.
Recently, we have worked with Scott Burks and Joe Frank from the Clinical Center at NIH. They are able to use pulsed focused ultrasound to alter tissues to recruit more MSCs. We tested pulsed focused ultrasound in a cisplatin model. Cisplatin is a treatment for some types of cancer but often causes kidney injury. Pulsed focused ultrasound guided MSC treatment reduced damage from cisplatin.