How to direct stem cells to the right place
Small molecules for "GPS navigation" of stem cells
Nanonewsnet based on Brigham and Women's Hospital: Small molecule helps get stem cells to sites of disease and damageBioengineers from Brigham and Women's Hospital (BWH) and employees of the pharmaceutical company Sanofi have found small molecules that can be used to "accompany" stem cells to the site of injury, disease or inflammation.
In addition, by offering a new strategy for targeted cell delivery, the methods themselves used to search for and test these low-molecular compounds can become important tools in the further development of cell therapy. The results of the work are published in the online edition of the journal Cell Reports (Long et al., A Small-Molecule Screen for Enhanced Homing of Systematically Infused Cells).
The researchers tested more than 9,000 compounds, and using a multi–step approach – including sophisticated microfluidic devices and new imaging technologies - narrowed the search area to test the most promising ones found.
"We have a lot of techniques and tools at our disposal that can be used to manipulate cells outside the body and make them do almost everything they need to, but as soon as we transplant cells, we lose full control over them," says study co–author Jeff Karp, PhD, associate professor BWH, Harvard Medical School, Senior lecturer at the Harvard Stem Cell Institute. "Thanks to this collaboration, we were able to find small molecules that can be used to process cells outside the body and program them to target blood vessels in affected or damaged tissues."
Small molecules give scientists several advantages, including the ability to use one of the safe and relatively simple procedures for pretreatment of cells before their intravenous administration.
"We are in dire need of strategies that would increase the clinical significance of cell therapy," says study co–author Oren Levy, PhD, lecturer in medicine at BWH. "What is needed to realize the hopes associated with cell therapy is precisely the development of a safe, cost-effective and easy-to-use engineering strategy."
Earlier, Dr. Karp and his colleagues from BWH found that bioengineering methods can be used to chemically bind molecules – "GPS navigators" that guide this cell to the inflammation zone - to the cell surface. The data they obtained confirmed the possibility of targeted cell delivery.
"At BWH we have laid the foundations. Our colleagues from Sanofi have extensive experience in screening small molecules, have a deep understanding of biology and are aware of unmet needs. In addition, they have a wonderful opportunity to transfer new medicines to the clinic," says Dr. Karp.
Scientists have found a low-molecular compound with which to carry out targeted delivery
mesenchymal stem cells (blue and green) in the area of tissue damage or inflammation.
(Photo: Oren Levy, Brigham and Women's Hospital).
In the search for compounds that activate control molecules on the surface of mesenchymal stem cells (MSCs), a group from Sanofi screened thousands of compounds, while confirming that the active substances they found did not change the viability of mesenchymal stromal cells or the profile of secreted immunomodulatory protein factors.
Currently, clinical trials of more than 450 methods of using MSCs for the treatment of a number of diseases, including myocardial infarction, Crohn's disease, lupus, multiple sclerosis, etc., are ongoing or have already been completed, but many of the tested methods do not become clinical methods of treatment. One of the key problems here was and remains the targeted delivery of the MSC (and their long stay there) to the places of damage.
Researchers have identified six of the most powerful and promising molecules, including a compound known as RO-31–8425. Then, after treating the cells with them, Dr. Karp's laboratory tested these compounds using a microfluidic device – a slide with tiny channels, the size of which is sufficient for only a small group of cells to pass through them at one time. The channels of the microfluidic device were covered with so-called intracellular Adhesion Molecules (ICAM-1) present on the surface of blood vessels in inflamed tissue. The pretreated Ro-31–8425 cells were stuck – an indicator of their ability to "homing" in areas of inflammation.
The researchers also tested their results on animal models. They systematically injected pretreated Ro-31–8425 cells into mice with one inflamed ear. Using optical imaging techniques (in particular, lifetime microscopy) they were convinced that the cells treated with this compound not only accumulated and remained in the inflamed ear, but also reduced inflammation.
"A unique opportunity to achieve this result was given to us by cooperation with our partners from both industry and academic science," Dr. Krap sums up. "Together we are solving one of the main problems facing cell therapy – the problem of targeted delivery of stem cells."
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