An inventive experimental design reveals, in real-time and at the scale of a single molecule, how stem cells slow down their rolling inside the circulatory system by developing long tethers that bind to the inner surfaces of blood vessels. The approach aids scientists enhance stem cell transplantations along with discovering novel treatments for metastasizing cancers.
Research conducted at KAUST aims to improve how stem cells move in the body so that they can reach where they are needed following transplantation. Image Credit: © 2021 King Abdullah University of Science & Technology; Anastasia Serin.
Most cells in the human body migrate from one organ to another through blood vessels to perform specific functions. For instance, cancer cells spread to new organs and immune cells move to inflamed tissues. Stem cells too migrate to new locations to transform into various tissues.
This stem cell ‘homing,’ where cells migrate to their new place of residence, is also essential for successful bone marrow transplantation for treating various diseases.”
Satoshi Habuchi, King Abdullah University of Science and Technology
Satoshi Habuchi had headed the research.
Homing is a multistep process during which cells gradually roll over the inner lining of blood vessels and later adhere to the lining upon reaching the destined site. Finally, they transmigrate across the vessel wall into the tissue.
The fact that homing cells develop tethers constituting ligands that sense and attach to adhesion molecules on the blood vessel lining was known to researchers. However, to date, they were not able to directly envision the rolling to comprehend precisely the processes at the molecular level.
Satoshi, Merzaban, and their group replicated cell rolling employing a microfluidic system.
The tethering and rolling step of homing had previously been described as a simple binding between selectins on the endothelium and their ligands on stem cells. Our findings demonstrated that the initial step of homing is far more dynamic and complicated.”
Bader Al Alwan, PhD Student, King Abdullah University of Science and Technology
The researchers identified that individual microvilli on the surface of the homing cells lengthen to form individual tethers. Ligands in the microvilli quickly elongate throughout the tethers so they can “sniff out” selectin in the blood vessel lining. Upon locating the selectins, the ligands attached to them, binding the tether to the vessel lining.
The binding helps resist the whole strength of the blood flow. It rolls forward due to the pressure exerted by the blood flow on top of the cell. The tether is stretched until it attains a crucial point when it breaks and flips forward to come in front of the cell. The sling, as addressed now, slows down the cell so that it can find the molecules that signal the location of its new home.
Al Alwan states, “When we started, we did not expect that cell morphology played such a critical role in stabilizing cell rolling. We were also surprised by the extent to which the morphology changes, with some tethers merging into multiple ones and others stretching to more than ten times the length of the cell.”
Our research is focused on understanding how various cells move in the body using adhesion systems. For example, one goal is to improve stem cell movement in the body so they can get where they are needed following transplantation or in other disease settings. We are also focused on understanding how and why cancer cells outperform normal cells in their ability to migrate so that we can develop methods to inhibit their metastasis.”
Jasmeen Merzaban, Study Co-Principal Investigator and Bioscientist, King Abdullah University of Science and Technology
“Using the sophisticated assays developed by Satoshi and his team, we also want to create a more precise map of the proteins that are present at each step of the homing and migration process to identify when and where they are important during migration,” concludes Jasmeen Merzaban.
The complex dynamics of stem-cell tethers and slings
KAUST scientists conduct experiments that may help to improve stem cell transplantations and to find new treatments for metastasizing cancers. Video Credit: © 2021 King Abdullah University of Science & Technology; Anastasia Serin.
Al Alwan, B., et al. (2021) Single-molecule imaging and microfluidic platform reveal molecular mechanisms of leukemic cell rolling. Communications Biology. doi.org/10.1038/s42003-021-02398-2.