Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, USC
Research TopicsStem Cells, Cancer, Hematopoiesis, Single Cell Analysis, Clonal Tracking, Systems Biology
Research OverviewMany tissues and organs are composed of short-lived cells that are continuously replenished under normal physiological conditions. This process relies on stem cells that can also regenerate tissue after injury. Regeneration is a concerted effort involving multiple stem cells. While individual stem cells may be differentially regulated, their overall activities must be strictly coordinated to ensure proper tissue size and function. Cellular heterogeneity and defects in cellular coordination are major hurdles in treating many diseases including cancer. Our lab is interested in understanding stem cell and cancer at the single cell level.
Stem cell coordination and regulation are particularly challenging for tissues with fast cellular turnover, such as blood. In an adult human, tens of thousands of hematopoietic stem cells (HSCs) together produce more than a hundred billion blood cells every day. Blood can be easily sampled, and its circulation ensures that a sampling faithfully represents the contributions of all stem cells. These unique characteristics make HSCs an optimal model for studying stem cell coordination and regulation. In addition to their scientific significance, HSC studies also possess immediate clinical impact. HSCs play a pivotal role in bone marrow transplantation, the earliest and by far the most prevalent stem cell therapy. Much research remains to be done as bone marrow transplantation is a risky procedure reserved only for patients with life-threatening diseases.
Our recent studies show that HSC differentiation is substantially altered by the conditioning regimen using during the transplantation. If a recipient is treated with conditioning such as irradiation prior to transplantation, individual HSCs produce distinct numbers of blood cells and differentially supply different cell types. This HSC coordination pattern persists throughout the recipient’s lifetime. In contrast, in the absence of pre-transplantation conditioning, individual HSCs uniformly supply the blood. We have also found that changes to HSC coordination are not random or stochastic, but instead are rigorously regulated at distinct steps of HSC differentiation. These findings are undetectable at the population level and provide a new framework for understanding stem cell regulation and tissue regeneration at the single cell level.
Our research is driven by three major areas of interest: (1) How are individual HSCs regulated to produce different amounts and types of blood cells? And how can we exploit the mechanisms underlying the cellular differences to control the overall stem cell population and to improve bone marrow transplantation? (2) How are distinct HSCs coordinated to ensure an overall balanced blood supply? And how does miscommunication between stem cells cause diseases? (3) How do individual cell clones differentially contribute to cancer genesis, metastasis and relapse? And how to design therapeutic treatments that target the responsible clones?
To address these questions, our multidisciplinary group specializes in single cell analysis that integrates research strategies from molecular biology, cell biology, systems biology, genetics, and bioinformatics. Our goal is to understand stem cell and cancer biology at the single cell level in order to provide new insights into the origins of disease and to identify new therapeutic targets.