Hematopoietic stem cell (HSC) fate decisions at least in part determine cellular composition of the hematopoietic system. It is known that differentiated blood cells produce ligands that act on HSCs to influence HSC fate. However, fundamentals underlying the feedback regulation of HSC fate are poorly understood. Here, we explored the fundamentals of the feedback regulation of HSC fate at the microenvironmental, intercellular (between cells), and intracellular (inside a cell) levels. First, we developed a machine learning algorithm to decompose heterogeneous blood cell samples isolated from cell culture. The results suggest the microenvironmental condition in which HSCs reside affects their transcriptional program. Further, we explicitly mapped feedback signals from 11 differentiated blood cells to HSCs by integrating microarray data, bioinformatics databases, and high content in vitro screening data. The results demonstrate the existence of blood cell type-specific feedback effect on HSC fate decisions. Intriguingly, we found that HSC self-renewal inducing ligands and proliferation inducing ligands were enriched in the NF-κB pathway and the STAT3 pathway, respectively. We constructed a kinetic model of the NF-κB – STAT3 pathway. The model serves a foundation for future development and optimization, and the final model could generate hypotheses of extracellular and intracellular intervention for controlling in vitro HSC expansion. Overall, this work has laid a conceptual and technical foundation for investigating cell-cell communication in other multicellular dynamic systems; one important application is in the use of cell-cell communication as a therapeutic avenue to treat various diseases.Ph.D
