The Signer Laboratory investigates stem cells at the interface of regenerative medicine and cancer biology. Stem cells reside in many of our tissues and organs throughout life. These rare stem cells have the remarkable potential to regenerate many of the specialized cells in our bodies after they are lost to normal wear and tear, injury and disease. Declines in stem cell function can lead to the onset of degenerative diseases. Overactivation or hijacking of stem cell activity can lead to uncontrolled growth and cancer. By unlocking the mysteries of stem cells, we expect to make breakthroughs that allow us to harness the regenerative potential of stem cells to treat degenerative diseases and identify new therapeutic targets to eradicate cancer.

Picture1Picture4Keeping stem cells fit
How do stem cells stay fit? A new breakthrough from our lab published in Cell Stem Cell, revealed that cell culture rapidly and massively increases protein synthesis within blood-forming stem cells. This enormous protein stress contributes to the inability to grow and expand these stem cells outside the body, which has limited their availability for patients that could benefit from stem cell transplants. To cope with this stress, stem cells activate the gene Hsf1 , which helps restore equilibrium and maintain stem cell fitness. Small molecules that super-activate Hsf1 enable us to grow high-quality stem cells for prolonged periods. We also found that Hsf1 gets activated within stem cells during aging to keep them fit throughout life. These discoveries will hopefully improve clinical outcomes for patients in need of stem cell transplants and could one day be leveraged to prevent blood disorders and boost immunity in older adults.

The science of tidying upPicture3
Why are stem cells so sensitive to protein stress? Recent discoveries from our research reveal that stem cells produce fewer misfolded proteins than other cells. We discovered that even a modest accumulation of misfolded proteins impairs the regenerative activity of stem cells. Misfolded proteins can contribute to the development of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Our discoveries raise the possibility that misfolded proteins may also be at the root of many other types of degenerative, malignant and age-related diseases.

Stem cells are lost in translationPicture2
Translation, the process of protein synthesis, has long been thought of as a housekeeping function, performed similarly by most cells. We broke that paradigm using a new technology that allowed for the quantification of protein synthesis within single cells in vivo. Using this technology we discovered that hematopoietic (blood forming) stem cells in the bone marrow synthesize new proteins much more slowly than other types of blood cells. Furthermore, we determined that low protein synthesis is crucial for maintaining the regenerative activity of hematopoietic stem cells. This was a novel and conceptually important mechanism not previously known to regulate stem cells. Building upon this discovery, it is now known that low protein synthesis is a broadly conserved feature of somatic stem cells that promotes regeneration in multiple tissues. These discoveries, which were published in Nature, uncovered a new world of biology that has set the stage for our current studies.

We continue to address the fundamental question of how cell-type specific differences in the regulation of protein homeostasis uniquely support stem cell maintenance and longevity, enhance tissue regeneration, suppress cancer, and promote healthy aging.


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s