Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape of highly purified human bone marrow HSCs displaying varying degrees of dormancy. We identify the orphan receptor GPRC5C, which enriches for dormant human HSCs. GPRC5C is also essential for HSC function, as demonstrated by genetic loss- and gain-of-function analyses. Through structural modelling and biochemical assays, we show that hyaluronic acid, a bone marrow extracellular matrix component, preserves dormancy through GPRC5C. We identify the hyaluronic acid–GPRC5C signalling axis controlling the state of dormancy in mouse and human HSCs.

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Hematopoietic stem cells (HSCs) hold the unique capacity to restore the entire blood system throughout life. To preserve life-long stem cell functionality, metabolic, epigenetic and transcriptional drivers form complex regulatory networks to tightly regulate HSCs. This interplay can be controlled by single metabolites, especially vitamins, instructing those epigenetic and transcriptional attributes. A non-classical retinoic acid (RA) signaling axis has been shown to be indispensable for protection of stem cell features in HSCs.