Shedding light on HSC dormancy—a role for the DARC

Hematopoietic stem cell (HSC) quiescence is vital for lifelong hematopoiesis as it maintains long-term potential and self-renewal capacity of HSCs. Hypoxia is one feature of the bone marrow (BM) microenvironment thought to contribute to quiescence by limiting oxidative stress and initiating a distinct metabolic program (1). Based on their prior identification of a hypoxia response element in the promoter region of the tetraspanin CD82 gene (2), Hur and colleagues sought to address the role of this molecule in HSC function (3). Consistent with hypoxia inducible factor 1 (HIF-1α) expression (4), long term-HSCs (LT-HSCs) were found to be the exclusive primitive hematopoietic cell type expressing CD82. Expression of CD82 initiated a dormancy-enforcing program dependent upon TGFβ signaling. Furthermore, CD82 expression on HSCs was maintained by a subset of macrophages (MΦs), an emerging niche cell for HSCs. Hematopoietic demands that occur as a result of injury or infection must interrupt dormancy-enforcing programs. As MΦs are important immune sentinels, the study suggests MΦs may directly control HSC function in demand-adapted hematopoiesis and in conditions of acute or chronic inflammation (5). Thus, the insights provided by Hur et al. have broad implications for understanding HSC function in demand-adapted hematopoiesis, as well as aging and cancer.