Under Homeostatic Conditions, a Balance is Maintained Between Two Pools of HSCs. The quiescent pool is characterized by high self-renewal, low cell cycling activity (top panel). To maintain steady state, some HSCs exit the quiescent pool and begin to actively cycle and differentiate (top panel). Treatment with INFα changes the dynamics by stimulating quiescent cells to enter the cycling/differentiating pool (bottom panel). The response of quiescent HSCs to INFα involves both positive and negative regulatory elements. Binding of INFα to its receptor (IFNAR) stimulates a signaling cascade that results in phosphorylation of STAT-1 and -2 which then participate in HSC activation in two ways: 1) they phosphorylate other factors involved in proliferation, and 2) they form a complex with interferon regulator factor 9 (the trimolecular complex is called interferon-stimulated gene factor-3, ISGF3) that binds to the interferon-stimulated responsive element (ISRE) in genes whose transcription is regulated by INF. A negative regulator, interferon regulatory factor 2 (IRF2), also effects INFα homeostasis by competing with IRF9 for binding to the ISRE. Because IRF2 lacks binding sites for STATs, it cannot form an ISGF3 and therefore does not support transcription. Inactivation of IRF2 results in depletion of the dormant HSC pool because constitutively generated INFα activity proceeds unopposed. Chronic treatment with INFα leads to exhaustion of the quiescent HSC pool (bottom panel).