Hematopoietic stem cells (HSCs) are immature progenitor cells that can generate all blood cells found in our body. HSCs are maintained throughout life by a division called self-renewal, in which a stem cell gives rise to at least one stem cell with the same developmental potential as the mother stem cells. HSCs can generate different types of blood cells, such as red blood cells and lymphocytes, via a property called multipotency. Thus, both the self-renewal and multipotency of HSCs is the key for blood homeostasis and regeneration. We are interested in understanding how these properties are regulated to maintain homeostasis and activated upon stress or injury. The self-renewal ability is often over-activated, while differentiation is suppressed in cancer. Thus, we also study how blood cancers (leukemia) inappropriately activate self-renewal program and disables differentiation.
Regulation of Hematopoietic Stem Cells by Systemic Factors and the Microenvironment
HSCs divide rarely (a feature called quiescence) but become activated and divide frequently upon stress, such as infection or injury, in order to facilitate immune responses or to promote hematopoietic regeneration. We discovered that a female sex hormone estrogen stimulates HSC division, and that estrogen promotes HSC division and red blood cell production during pregnancy (Nakada et al., Nature. 2014). More recently, we discovered that estrogen activates the unfolded protein response (UPR) in HSCs, endowing them with increased capacity to cope with stress and to promote regeneration (Chapple et al., eLife. 2018). We are using a combination of approaches, including transplantation, epigenome profiling, and CRISPR-mediated gene editing, to understand how estrogen stimulates HSCs.
Metabolism in Leukemia Stem Cells
Cancer cells often exhibit aberrant metabolic regulation, such as high dependence on glucose or glutamine metabolism. We are interested in identifying metabolic regulations that are important in leukemia cells but are less important in HSCs and normal hematopoietic cells. We identified a metabolic master regulator for cancer cells that is dispensable for normal HSCs, called AMPK (Saito et al., Cell Stem Cell. 2015). AMPK was particularly important for the immature leukemia cells called leukemia stem cells, and inhibiting this pathway rendered leukemia stem cells unfit to reside in the hypoxic bone marrow environment leading to their demise. Our ongoing work has revealed that AMPK has pervasive effects on leukemia stem cells beyond metabolism, such as gene regulation.
Development of New Genetic Models of Hematological Malignancies
Recent advances in genome editing tools, in particular the CRISPR/Cas9 system, has transformed the way in which genetic studies are performed in multiple model systems. However, until recently, performing genome editing in primary HSCs remained challenging. We recently developed a method to directly modify the genomes of both mouse and human HSCs using the CRISPR/Cas9 system (Gundry et al., Cell Reports. 2016). With this method, we were able to delete genes in more than 75 percent of HSCs to evaluate gene function in primary HSCs. Moreover, we further optimized the method to perform multiplexed genome editing of mouse HSCs and demonstrated that this method can be used to generate novel mouse models of acute myeloid leukemias by combinatorially deleting up to five genes recurrently mutated in human leukemias (Shi et al. In press). We are using this method to create new leukemia models to better understand how mutations cooperate to transform hematopoietic progenitor cells.