First came transparent brain tissue, then mostly transparent mice. Now, researchers at Caltech have applied a tissue-clearing technique to make bones see-through. The process provides valuable insight into how stem cells function inside skeletons, and could lead to better treatment for degenerative conditions such as osteoporosis.
The bones in our body are constantly undergoing a process of degradation and rebuilding. In fact, according to Caltech, the skeleton you have now is not the same one you had 10 years ago. This process is, in part, controlled by stem cells in the bone marrow called osteoprogenitors. Till now, the only way to check on the function of these cells was to cut bone into cross sections. But, because the stem cells aren't found everywhere in the marrow, it was a bit of a hit-and-miss endeavor.
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"Because of the sparsity of the stem cell population in the bone, it is challenging to extrapolate their numbers and positions from just a few slices of bone," says Alon Greenbaum, co-first author on a paper about the research published in Science Translational Medicine. "Additionally, slicing into bone causes deterioration and loses the complex and three-dimensional environment of the stem cell inside the bone. So there is a need to see inside intact tissue."
To give them that kind of a view of bones, the team turned to a technique developed at Stanford University called CLARITY, which was originally used to make a mouse's brain transparent.
In this case, the researchers removed calcium and lipids from mouse bones, two components that make them opaque. To provide the structural support needed after the lipids were removed, a clear hydrogel was injected. Once the process was complete, the bones appeared transparent to the naked eye and revealed stem cells the researchers had engineered to glow red.
The researchers then used the technique to verify the action of a new drug designed to treat osteoporosis made by the biotechnology company Amgen. In tests, mice examined with the new technique – dubbed Bone CLARITY – who had received the drug showed an increase in stem cell proliferation in their vertebrae, while those left untreated did not.
"Monitoring stem-cell responses to these kinds of drugs is crucial because early increases in proliferation are expected while new bone is being built, but long-term proliferation can lead to cancer," said says Ken Chan, graduate student and co-first author of the paper.
"Biologists are beginning to discover that bones are not just structural supports," added Viviana Gradinaru, whose lab conducted the study. "For example, hormones from bone send the brain signals to regulate appetite, and studying the interface between the skull and the brain is a vital part of neuroscience. It is our hope that Bone CLARITY will help break new ground in understanding the inner workings of these important organs."