1. Hyaluronic acid–GPRC5C signalling promotes dormancy in haematopoietic stem cells
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Yu Wei Zhang, Julian Mess, Nadim Aizarani, Pankaj Mishra, Carys Johnson, Mari Carmen Romero-Mulero, Jasmin Rettkowski, Katharina Schönberger, Nadine Obier, Karin Jäcklein, Nadine M. Woessner, Maria-Eleni Lalioti, Talia Velasco-Hernandez, Katarzyna Sikora, Ralph Wäsch, Bernhard Lehnertz, Guy Sauvageau, Thomas Manke, Pablo Menendez, Sebastian Gottfried Walter, Susana Minguet, Elisa Laurenti, Stefan Günther, Dominic Grün, and Nina Cabezas-Wallscheid
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Cell Biology - Abstract
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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