Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells.
Yu Wei ZhangJulian MessNadim AizaraniPankaj MishraCarys JohnsonMari Carmen Romero-MuleroJasmin RettkowskiKatharina SchönbergerNadine ObierKarin JäckleinNadine M WoessnerMaria-Eleni LaliotiTalia Velasco-HernandezKatarzyna SikoraRalph WäschBernhard LehnertzGuy SauvageauThomas MankePablo MenendezSebastian Gottfried WalterSusana MinguetElisa LaurentiStefan GüntherDominic GrünNina Cabezas-WallscheidPublished in: Nature cell biology (2022)
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.
Keyphrases
- hyaluronic acid
- bone marrow
- stem cells
- single cell
- endothelial cells
- extracellular matrix
- mesenchymal stem cells
- induced pluripotent stem cells
- pluripotent stem cells
- rna seq
- high throughput
- type diabetes
- gene expression
- cell therapy
- genome wide
- high fat diet induced
- skeletal muscle
- dna methylation
- copy number
- binding protein