Single-cell RNA-seq analysis uncovers hypoxia-induced changes in hematopoietic stem cells and fate decisions of progenitors

Abstract Hypoxia is a common phenomenon in about 5–10% of the world's population who maladapted to the high altitude environment. Hypoxia is associated with multiple pathophysiological processes, among which hematologic problems are the best-known. However, the underlying molecular mechanism remains unclear, especially in the early stage of hematopoiesis. Single-cell RNA sequencing (scRNA-seq) captures instantaneous transitions between different states of the cell population and can therefore be employed to enhance our understanding of cell fate choices in hematopoiesis. In this study, hematopoietic stem cells and their progeny were collected in homeostasis as the control group and after 13 days of exposure to hypoxia as the treatment group. scRNA-seq was employed to establish an atlas of hematopoietic stem progenitor cells and identify differences in the choice of cell fate. 4,909 and 3,482 cells were obtained in hypoxia and control groups, respectively. An atlas was established, and 14 cell types were identified. After hypoxic treatment, trajectory analysis found a bias toward erythroid and mononuclear lineages, and cell cycle genes are more likely to be involved in erythropoiesis. Cell communication in the niche was explored, and mesenchymal stem cells were found to be related to mononuclear differentiation and mobilization. In addition, stem cells were increased in the quiescent state. These findings highlight the influence of hematopoiesis in the bone marrow when the body overcomes hypoxia, and provide new clues on the molecular mechanism of maladaptation to high altitudes.