Stress and Distress of Hematopoietic Stem Cells

Hematopoietic Stem Cells (HSCs) are generating all types of blood and immune cells. They regenerate along healthy life, and even more so following immunological stimuli. We can prospectively isolate naïve-HSCs; however, there is little understanding of immune-activated HSCs. Part of the difficulties come from usage of multiple surface-markers, some of which are changing drastically after stimuli. The Fgd5-mCherry reporter mouse allow better identification of HSCs. Importantly, we observed no significant changes in frequencies, and total-numbers, of the primitive HSCs (lineage^-cKit⁺ Sca1⁺CD150⁺Fgd5mCherry⁺) within the bone-marrow upon acute or extended immune-stimulation by pIpC. Furthermore, we found that these Fgd5+ HSCs retained robust long-term multipotent activity, while adjacent LSKCD150+Fgd5mCherry- do not. RNA-Seq analysis revealed differently expressed surface markers, including CD317 and CD69, being the first HSC-activation markers. CD317 reveal that all HSCs are rapidly responding to stimuli, while CD69 suggest differences of further activation. Furthermore, chronic long-term immune stimulation exerts deleterious effects on HSCs, and may predispose toward malignancy. We are also interested in various types of immune stimuli that broaden understanding of HSCs as part of the immune system. Understanding HSC’s activation is suggesting the opportunity to enhance a needed response, or to blunt an excessive activation that may lead to exhaustion.