Stem Cell Research and the Effect of Usp16 on Down Syndrome Characteristics

Image of embryonic stem cells

Stem Cell Research and the Effect of Usp16 on Down Syndrome Characteristics

In recent years, the importance and diverse impacts of stem cell research have been a central subject for scientists from a variety of fields. One of those fields is Down Syndrome (DS) research. Current DS research, among other topics, is exploring the connection between neural stem cell deficits, intellectual disability, impaired motor function and premature aging processes commonly seen in individuals affected by DS.

Before diving into the research findings, however, we will first provide some background information on stem cells and stem cell deficits in DS. Stem cells are undifferentiated cells—meaning that they can develop into different kinds of specific cells, or they can divide to make more of themselves to maintain the stem cell pool. Stem cells are extremely important because they are essentially the body’s raw materials from which all other cells with specific functions are made. Stem cells are crucial during development, but they also exist in various parts of the adult body and act as an internal repair system for a person’s entire life. 

The fertilized egg is the ultimate stem cell in that it can produce all of the different cell types in the body. Early in development, stem cells become more restricted and mature into cell populations that serve the needs of specific tissues. Blood, for example, forms from stem cells in the bone marrow, and neural stem cells differentiate into the many types of cells that make up the brain. We have been investigating the development of one part of the brain called the cerebellum, which is at the back of your head. The cerebellum contains about half of the total number of brain cells despite accounting for only about 10% of the brain’s total weight. The main cells that neural stem cells produce in the cerebellum are called “granule cells,” and they play a crucial role in coordinating movements. Hence, the cerebellum is extremely important for motor skills. The cerebellums of individuals with DS are generally smaller than those found in normally developing people. These smaller cerebellums contain far fewer granule cells that can make up the neural circuits responsible for coordinating movements and learning new motor patterns. Additionally, individuals with DS may experience premature aging-related conditions that could be due to an issue with their stem cells. A defect in stem cells’ ability to self-renew would hamper the body’s ability to repair itself, which is essentially what happens much later in life for all individuals, but it might be happening earlier in persons with DS. 

 A major study conducted at our Stanford University Down Syndrome Center by Dr. Maddalena Adorno discovered a likely mechanism explaining howneural stem cells are impaired in individuals with DS. One of the chromosome 21 genes that is triplicated in DS is called Usp16. The over-expression of this gene in DS antagonizes the effects of another gene called Bmi1. Bmi1 promotes renewal in stem cells whereas Usp16 promotes differentiation. Without renewal, the stem cell pool can become depleted. In addition, Usp16 also affects a wide range of regulatory processes such as the maintenance of bone.  

 In Adorno’s study, Ts65Dn mice were engineered to have two copies of Usp16 instead of three, while still having three copies of most of the other genes similar to those found on human chromosome 21. The results were remarkable. Adorno discovered that removing one copy of Usp16 rescued the stem cell impairments seen in this mouse model of DS. The neural stem cells from these mice were better able to renew. Further studies on these mice showed that they had improved learning ability, they had better balance and gait, and they had improved bone health. These results support the hypothesis that Usp16 is associated with aging-related deficits due to stem cell impairments in DS. While it is possible to eliminate one copy of Usp16 in mice, it is unlikely that such a procedure will be possible in humans, at least in the foreseeable future.  With that said, Usp16 exerts many of its actions through down-stream regulatory pathways, and it could be possible to intervene in those pathways pharmacologically. Further experiments are currently being done to explore the mechanisms of action of Usp16 with the hope of finding new therapeutic strategies to improve the health and well-being of individuals who have DS.