BIOPHYSICS SEMINAR<br>Systems Analysis of Mouse Hematopoietic Stem Cells <i>In Vivo</i> at the Single Cell Level

Hematopoietic stem cells (HSCs) sustain the blood and immune systems through a complex differentiation process. While this process has been extensively characterized at the population level, little is known about the lineage commitment of individual HSCs. In particular, how these stem cells, few in number and residing in different bones, are coordinated in regenerating a common blood pool remains an unsolved question. To address this question, we have recently developed a single cell tracking system using genetic barcodes and high-throughput sequencing. This experimental system provides the first single cell perspective of in vivo HSC differentiation. We show that individual HSCs follow distinct and mutually compensating lineage commitment paths that diverge at defined differentiation stages and lead to the production of distinct quantities and varieties of blood cells. In preconditioned mice used in virtually all HSC studies, a small subset of HSCs produces the majority of blood cells. Moreover, individual HSCs differentially contribute to various types of blood cells. Conversely, when mice are not conditioned, all HSCs uniformly differentiate and equally contribute to measured blood lineages. This surprising contrast, along with other findings that I will present, is unexpected and unobtainable from conventional studies. Our results demonstrate the compelling synergy between systems biology and single cell analysis, and provide a new approach to studying stem cells and tissue regeneration at a refined resolution.

Irving L. Weissman Lab
Institute for Stem Cell Biology and Regenerative Medicine
Stanford University School of Medicine