Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution
Jing Cao1, Qi Jason Yao2, Jiao Wu1
1State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PRC; Shanghai Key Laboratory of Gynecologic Oncology, Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PRC; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PRC.
Abstract:
Metabolic status is crucial for stem cell functions; however, the metabolic heterogeneity of endogenous stem cells has never been directly assessed. Here, we develop a platform for high-throughput single-cell metabolomics (hi-scMet) of hematopoietic stem cells (HSCs). By combining flow cytometric isolation and nanoparticle-enhanced laser desorption/ionization mass spectrometry, we routinely detected >100 features from single cells. We mapped the single-cell metabolomes of all hematopoietic cell populations and HSC subpopulations with different division times, detecting 33 features whose levels exhibited trending changes during HSC proliferation. We found progressive activation of the oxidative pentose phosphate pathway (OxiPPP) from dormant to active HSCs. Genetic or pharmacological interference with OxiPPP increased reactive oxygen species level in HSCs, reducing HSC self-renewal upon oxidative stress. Together, our work uncovers the metabolic dynamics during HSC proliferation, reveals a role of OxiPPP for HSC activation, and illustrates the utility of hi-scMet in dissecting metabolic heterogeneity of immunophenotypically defined cell populations.
