Recent research has identified a novel molecule that could help localise stem cells within the body. Cell therapy holds significant promise for treating a wide range of diseases and tissue defects including arthritis, cardiovascular disease, multiple sclerosis and Crohn’s disease. But in current therapies, most cell types do not reach diseased or damaged tissues efficiently.
Controlling cells once they have been introduced into the body is a key challenge to overcome. There are all kinds of tools and techniques that can be used to manipulate cells outside of the body in a petri dish and get them to do almost anything we want. But once cells have been transplanted, it is difficult to control them.
We have now been able to identify small molecules that can be used to treat cells before injection into the body, programming them to target blood vessels in diseased or damaged tissue once inside the body.
This molecular targeting is especially important in the case of adult mesenchymal stem cells (MSCs), which are known to secrete several therapeutic factors and are being explored in more than 450 clinical trials. A major challenge has been getting MSCs to target – and stay at – sites of damage within the body, where they can secrete high levels of therapeutic factors to suppress inflammation and promote recovery.
Our team of bio-engineers from Brigham and Women’s Hospital and imaging experts at the Massachusetts General Hospital (led by Charles Lin), with collaborators at the pharmaceutical company Sanofi, has identified small molecules that can be used to program stem cells to home in on sites of damage, disease and inflammation.
We tested more than 9,000 compounds for their ability to send stem cells in the right direction. We used a multi-step approach – including a sophisticated micro-scale set up and a novel imaging technique – to select and test the most promising compounds.
A Molecular Navigation System
We had previously found that it is possible to use bioengineering techniques to chemically attach molecules to the surface of a cell, to act as a GPS, guiding the cell to the site of inflammation.
Screening thousands of compounds, looking for ones that activated key molecules on the surface of the MSCs, we found six promising molecules, including one known as Ro-31-8425, the most potent of the group. We treated cells with each of these promising molecules and then flowed the cells into microscale glass channels, to simulate the flow of cells in the bloodstream.
The glass channels were coated with a protein which is also found on the surface of blood vessels at inflamed tissue within the body. Cells pre-treated with Ro-31-8425 stuck to the coated channels – a sign that they might be able to home in on sites of inflammation.
The next step was to test our cells in an animal. We injected cells that had been pre-treated with Ro-31-8425 into the blood stream of a mouse with one inflamed ear. We then examined both ears using unique real-time microscopy, a technique that allows researchers to capture images of tissue in live animals. We observed that the cells treated with the compound not only homed in on the inflamed ear, but also reduced inflammation.
These findings, along with the multi-step screening platform we developed, have the potential to improve delivery of injected stem cells to sites of disease, where they can release their therapeutic cargo at high levels. This will greatly boost the clinical impact of cell-based therapies in treating life-threatening diseases.
Authors: Jeffrey Karp, Associate Professor of Medicine, Harvard Medical School and Oren Levy, Post-doctoral Researcher, Harvard Medical School. Top Photo: National Institutes of Health.