“Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” ——Sydney Brenner

The development of blood and immune system starts from hematopoietic stem cells (HSCs), following a series of cell fate decision events, ultimately giving rise to a complex defending system with distinct cell lineages. ‘How cell fate choice is regulated’ is a long-standing question in biology. At the molecular level, transcriptional and epigenetic networks define a specific phenotype of immune cells. At the cellular level, specialized cells integrate extracellular signals to establish stable cell fate. At the multicellular level, cell-cell interactions between tissue and immune cells coordinate and maintain tissue homeostasis.

Our previous research was focused on the development and application of novel lineage tracing technologies for understanding cell fate decision. We developed a barcode-based clonal lineage tracing approach, termed Polylox. Using the Polylox, we discovered that HSCs are comprised of subsets with different fate patterns: multilineage, myeloid-restricted and differentiation-inactive under steady-state (Nature, 2017; Nature Protocols, 2019). To decode the molecular programs that determine HSC fate, we developed the PolyExpress RNA barcoding system that enables paired analysis of cell fate and transcriptomes at single-cell resolution. Applying the PolyExpress, we identified potential HSC fate regulators (e.g. Hoxb2) in situ, providing a new entry point to investigate the molecular mechanism of cell fate choice (Cell Stem Cell, 2020).

By integrating developmental biology, immunology, systems biology and synthetic biology, we are developing multi-dimensional single-cell lineage tracing technologies, which aims to study cell fate regulation at genetic, epigenetic, transcriptional and spatial-temporal scales. Using novel single cell approaches, we will investigate the development and regeneration of the blood and immune system under physiological conditions and challenges such as cancer, viral infection and aging.