Our mission is to extend human healthspan. To do this, we study blood-forming stem cells. These very rare cells in the bone have three superpowers: (1) they self-renew to make more of themselves, (2) they can differentiate to produce any type of specialized blood or immune cells, (3) they have exceptional longevity. Throughout life, stem cells keep us healthy by regenerating all our blood and immune cells.

The problem is that stem cells can malfunction. If stem cells can’t replenish themselves through self-renewal, then we can’t regenerate and develop degenerative diseases like bone marrow failure. If our stem cells self-renew too much and we produce too many cells, we get cancer. If the stem cells produce cells in the wrong proportions, it can be disasterous. Too few red blood cells? Anemia. Too many inflammatory cells? Chronic inflammation. The wrong number of platelets? Clotting disorders. Too few B or T cells? We can become immune compromised.

All of these problems – they tend to occur with aging. So even though stem cells are hard-wired for longevity – they also age. We need to identify what gives stem cells their long life, understand where those systems breakdown, and we need to develop ways to intervene – to preserve stem cell fitness and health throughout life. This enables us to treat and prevent diseases at their root.

Our breakthrough research discovered blood-forming stem cells produce protein slower than other types of cells. Proteins are workhorses carrying out specialized jobs within cells. When proteins are produced too quickly, it leads to errors that cause them to malfunction, which severely impairs stem cells. By hacking the stem cell protein network we improve stem cell fitness, enhance tissue regeneration, and suppress cancer. By leveraging normal stem cells in our scientific process, we are unraveling the origin of diseases and the blueprint for longevity that is leading to the development of novel therapies to extend human healthspan and eliminate disease.

Stem cells are lost in translation

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.

The science of tidying up

Why are stem cells so sensitive to increased protein synthesis? 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, which can aggregate and become toxic, impairs the regenerative activity of stem cells.

Stem cells must take out the trash

Although stem cells produce less misfolded protein than most other cell types, some mistakes and damage are inevitable. In most cells, damaged or misfolded proteins are eliminated by the proteasome. But we found that stem cells have very little proteasome activity. If getting rid of misfolded proteins is so important to stem cells, how do stem cells take out their protein “trash” if proteasome activity is so low? Our latest breakthrough published in Cell Stem Cell, uncovered that stem cells use a different protein waste system entirely. Misfolded proteins are trafficked and corralled in cages called aggresomes, where they are collectively destroyed and recycled in a process called aggrephagy. Disabling the aggrephagy pathway causes stem cells to accumulate protein aggregates, which impairs their fitness and longevity. Furthermore, aging stem cells fail to form aggresomes, suggesting that the inability to destroy misfolded proteins may be a key contributing factor to the declining function of stem cells during aging. Disrupted protein homeostasis in stem cells may thus lie at the root of many degenerative, malignant and age-related blood diseases, and improving stem cells’ ability to eliminate misfolded proteins could mitigate age-associated blood and immune disorders.

Keeping 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.

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.