Fluorescent mouse tibia

Caltech researchers render live bones transparent

Image credit: Gradinaru laboratory/Caltech

A new imaging method which makes living bones transparent allows researchers to observe stem cells in live bone marrow.

Just like skin, hair and nails, healthy bone is constantly regenerating itself. This is controlled by a balance of processes which break down old bone and grow new tissue from stem cells in the bone marrow (osteorogenitors).

This delicate balance can be lost, with unpleasant consequences. For instance, osteoporosis – which affects elderly people in particular – is a disease which causes bone mass to be lost, leading to a higher risk of fractures. To monitor how potential therapeutics could improve the condition of people with osteoporosis more effectively, researchers must be able to observe stem cells within the bone.

However, populations are sparse and unevenly distributed through the bone.

“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,” said Alon Greenbaum, a researcher at California Institute of Technology (CalTech) and co-first author of the study.

“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.”

The team began with a method called Clarity, originally developed for clearing brain tissue. Clarity renders soft tissues transparent by removing lipids – opaque molecules – from cells while providing extra support using a clear hydrogen mesh.

Transparent mouse bones

Gradinaru laboratory/Caltech

Image credit: Gradinaru laboratory/Caltech

They worked with bones from dead mice, which had been genetically engineered to have their stem cells fluoresce in red. First, they removed calcium – which contributes to opacity and hardness – from the bones. Then, they infused the bone with a hydrogel, which preserves the internal structure of the bone. Finally, they washed away the lipids, leaving the bone transparent.

The transparent bone can be imaged using a custom microscope, which picks up the fluorescent red stem cells inside. 

The CalTech researchers named this new technique ‘Bone Clarity’. They used the method to test a potential new drug for osteoporosis and found that it was possible to monitor an increase in stem cell populations within the living bone.

The researchers hope that Bone Clarity could have applications in understanding how bones interact with the rest of the body.

“Biologists are beginning to discover that bones are not just structural supports,” says Dr Viviana Gradinaru, assistant professor of biology and biological engine. “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.”

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