Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells

Abstract

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

“…Moreover, cytokine stimulation induces HSCs to exit their quiescent state accompanied by induction of DNA damage in these cells. 15 In addition, culture of HSCs in cytokine cocktails required for VSV-G-LV transduction leads to loss of engraftment potential. Thus, H/F-LV mediates high transduction efficiency without compromising HSC engraftment, homing, and differentiation capacity.…”

“…39,57,58 In addition, the FA genetic defect makes the HSCs more fragile. 15,59 Therefore, it would be beneficial to transduce hCD34 1 cells directly in unfractionated FA BM aspirates. To preserve FA HSCs, they are currently transduced under low oxygen conditions before being reinfused into patients.…”

“…13,14 It was also shown that exit from dormancy provokes DNA damage-induced attrition in HSCs. 15 High hCD34 1 -cell transduction was achieved only by combining high VSV-G-LV doses with strong cytokine stimulation that increased the risk for multicopy integration. Insertional mutagenesis under these conditions cannot be excluded, 16,17 although current trials using LVs do not report adverse events.…”

The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence

“…Among their evolved adaptations are elaborate cellular protective programs that ensure stem cell integrity, tissue homeostasis, and organismal survival (Biteau, Hochmuth & Jasper, 2008; Brown et al., 2013; Ito et al., 2004; Rando, 2006; Renault et al., 2009; Rossi, Jamieson & Weissman, 2008; Rossi et al., 2007; Sahin & Depinho, 2010; Sperka, Wang & Rudolph, 2012; Walter et al., 2015). The mitochondrial unfolded protein response (UPR mt ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues (Berger et al., 2016; Mohrin et al., 2015; Zhang et al., 2016).…”

“…An alternative approach to model HSC proliferation in vivo is to treat mice with polyinosinic:polycytidylic acid (pIpC), a synthetic double‐stranded RNA (dsRNA) mimetic that stimulates the multiple immune signaling pathways that are activated during a viral infection (Walter et al., 2015). Compared to HSCs isolated from untreated mice, HSCs isolated from mice 24 hr after the pIpC treatment showed increased proliferation (Figure 2e) and mitochondrial mass (Figure 2f,g), and induction of the expression of oxidative phosphorylation genes (Figure 2h) and mitochondrial chaperones and proteases (Figure 2i).…”