Adult stem cells have the ability to transform into many types of tissues, but tracing the path individual stem cells follow because they mature and identifying the molecules that trigger these types of fateful decisions are difficult in a living animal.
University of California, Berkeley, neuroscientists have now combined new techniques for sequencing the RNA within single cells with detailed statistical analysis to easier track individual stem cells in the nose, uncovering hints that someday could help restore smell to those who have dropped it.
The results are published this week within the journal Cell Stem Cell .
“A stem cell’s job is twofold: to change or recreate mature cells that are lost over time, each through normal aging and after injury, and to replace on their own so that the process can continue over the life of the pet, ” said senior author John Ngai, the Coates Family Professor of Neuroscience and a member of UC Berkeley’s Helen Wills Neuroscience Institute and the Berkeley Stem Cellular Center. “We are getting closer to understanding how mature sensory neurons are generated from olfactory stem cells, an understanding absolutely key for an eventual stem cell therapy to restore perform. ”
Ngai noted that perhaps one-quarter of all people over the age of 50 have some loss of smell, however doctors have little understanding why, and no treatments for many cases. There’s not even a standardized test for lack of smell, as there is for vision or hearing reduction, in spite of widespread reports of suffering by patients that have lost their sense of smell.
“Some cases of anosmia — the loss of the sense associated with smell — are due to traumatic injury, and there is certainly generally not a whole lot you can do about that, ” he mentioned. “But some are age-related, or occur for factors we don’t quite know. In the case of age-related anosmias, it may be because the stem cells are just not doing their work replacing the cells that are naturally lost over time. One concept is that if we could harness the very stem cells which are in the noses of people who are losing smell, maybe we are able to figure out a way to restore function, by getting them to make the cells that are lost. ”
Monitoring cell fate
Ngai, who guides the Functional Genomics Laboratory in UC Berkeley’s Ca Institute for Quantitative Biosciences, focuses on the cells and regulating molecules involved in our sense of smell. Olfactory cellular material in the nose are unusual in that they are part of the system’s outer layer, or epithelium, but also part of the nervous program, incorporating neurons that connect directly with the smell facilities in the brain.
His group has been dealing with adult olfactory stem cells that give rise to the neurons that sense odors and other cells, such as sustentacular tissue, that support the neurons. A new technique for sequencing the particular RNA in a single cell has been revolutionary, Ngai said, permitting researchers to trace which stem cells in a densely packed tissues become specialized, based on the mRNA present in the cell, which usually indicates which genes are being expressed. Nevertheless, it is hard to follow stem cells that can potentially differentiate into various kinds of cells.
Ngai’s group teamed up with UC Berkeley statisticians and computer scientists — led simply by Sandrine Dudoit, a professor of biotstatistics and stats, Elizabeth Purdom, a professor of statistics, and Nir Yosef, a professor of electrical engineering and personal computer sciences — to develop a way to analyze the experimental information and identify cells with similar RNA profiles, a sign of specific cell types and developmental states.
As a result, the team was able to trace the pathways that cells take as they turn into sustentacular cells — which seems to be the default fate for olfactory originate cells — and into neurons and other types of cellular material. They also were able to identify a signaling pathway known as “Wnt” that triggers the olfactory stem cell to become a sensory neuron.
Ngai cautions that the immediate implications from the work are limited to animal models, which provide the required foundation for eventually addressing human anosmias. “But with this particular information, we now have a window into what controls the procedure and therefore a window into manipulating or coopting that will process to stimulate regeneration” he said. “There is a lot of work on Wnt signaling pathways, for example , so there are a great number of small-molecule drugs that could be tested to trigger a come cell to mature into a neuron. ”
The sequencing and statistical techniques the team created can also be used by others studying regulation of stem cellular material in other tissues, organ systems or organisms, he mentioned.