Ca2+tapulting HSCs into action

Abstract

In this issue of JEM, Umemoto et al. (https://doi.org/10.1084/jem.20180421) demonstrate that calcium influx stimulates mitochondrial metabolism and initiates proliferation in hematopoietic stem cells (HSCs). Extracellular adenosine, sourced from surrounding hematopoietic progenitors, inhibits this calcium influx, thereby suppressing mitochondrial metabolism and promoting HSC quiescence. This is the first demonstration that a calcium-mitochondria pathway regulates HSC division.

Insight from Andrew J. Finch, Amelie V. Guitart, and Kamil R. Kranc.

The role of the adenosine–|Ca²⁺→mitochondria axis in the regulation of HSC division. Left: Adenosine (ADO) through adenosine A2 receptor prevents calcium entry to maintain low mitochondrial membrane potential and sustain HSC quiescence. Right: TPO and SCF induce calcium influx in HSCs through L-type voltage-gated Ca²⁺ channel (VGCC), which in turn activates mitochondria, leading to HSC division. Ca²⁺ influx may also regulate multiple other targets, including CaM, calpains, and the PKC family members, to exert its functions in HSCs. This figure was created using the Servier Medical Art database (licensed under a Creative Commons Attribution 3.0 Unported License).

Adenosine maintains HSC quiescence in vivo. Under physiological condition, T reg cells, myeloid progenitors, endothelial cells, and mesenchymal stromal cells express ecto-5′-nucleotidase (CD73), which converts AMP to adenosine. Adenosine presence in the BM microenvironment is sensed by adenosine A2 receptor (A2R), thereby inhibiting influx of extracellular Ca²⁺ and promoting HSC quiescence. This figure was created using the Servier Medical Art database (licensed under a Creative Commons Attribution 3.0 Unported License).