Table 1.

Roles of stress-related pathways including the cGAS-STING pathway in regulating HSPC maintenance.

Species	Context	Target	Target cells	Outcome	Mechanism	Reference
Mouse	Homeostasis	cGAS-STING pathway	HSCs	Proliferation; Reduced self-renewal	Cia-cGAS is a suppressor of cGAS. Cia-cGAS deficiency results in the hyperactivation of cGAS-STING pathway and increased production of IFN-I.	(15)
Mouse	Homeostasis	cGAS-STING pathway	HSPCs	Proliferation	DDX41 insufficiency results in excessive R-loop accumulation, which subsequently activate cGAS-STING-NF-κB pathway to promote HSPC expansion.	(53)
Mouse	Homeostasis	cGAS-STING pathway	HSCs	Proliferation; Reduced self-renewal	Apoptotic caspases deficiency triggers the release of mtDNA, which induces the constitutive activation of cGAS-STING pathway and increased IFN-I production.	(54)
Mouse	c-di-GMP administration	cGAS-STING pathway	HSPCs	Proliferation; Myeloid-biased differentiation; Mobilization; Reduced self-renewal	Bacterial c-di-GMP activates STING pathway in a cGAS-independent manner, the downstream IRF3/IFN-I signaling induces HSPC proliferation and myeloid-biased differentiation but reduces HSC self-renewal and mobilization; the downstream NF-κB/G-CSF and JNK/TGF-β promotes HSC mobilization.	(55)
Mouse	Homeostasis	IRF1/IRF2	HSCs	Proliferation; Reduced self-renewal	IRF1 is a downstream effector of both cGAS-STING pathway and IFN-I signaling. IRF2 can repress IRF1 through competitively binding to the promoter of target genes. IRF1 activation or IRF2 deficiency will promote proliferation but reduce self-renewal of HSCs.	(56)
Mouse	Genotoxic stress (IR)	IRF5	HSPCs	Proliferation; Apoptosis	IRF5 is a downstream effector of both cGAS-STING pathway and IFN-I signaling. IRF5 is upregulated and may contribute to increased proliferation, replication stress, and apoptosis of HSPC after IR.	(57)
Mouse; Zebrafish	Homeostasis	IRF7	HSCs	Myeloid-biased differentiation; Reduced HSC development	IRF7 is a downstream effector of both cGAS-STING pathway and IFN-I signaling. IRF7 activation will reduce HSC formation in the AGM region and T cell differentiation of HSCs.	(58)
Human; Mouse	Infection; Inflammation	NF-κB	HSCs	Proliferation; Myeloid-biased differentiation; Reduced self-renewal	NF-κB is a main downstream effector of both cGAS-STING pathway and cytokine signaling such as IL1 and TNF. NF-κB can induce the transcriptional activation of myeloid transcription factor PU.1.	(59–62)
Mouse	Homeostasis	TRAF6/IKK/NF-κB	HSCs	Proliferation; Myeloid-biased differentiation; Reduced self-renewal	TRAF6 or IKK deficiency-induced reduction of basal NF-κB signaling can promote proliferation and myeloid-biased differentiation but reduce self-renewal of HSCs.	(63)
Human; Mouse	Homeostasis; Stress	mTOR or MAPKs	HSCs	Proliferation; Myeloid-biased differentiation; Reduced self-renewal	mTOR or MAPKs signaling activation is associated with increased proliferation and myeloid-biased differentiation, but reduced self-renewal of HSCs.	(29, 64–66)
Mouse	pI:C administration	IFN-I signaling	HSPCs	Proliferation; Myeloid-biased differentiation	Acute IFN-I signaling activates STAT1 and Akt/mTOR to upregulate the expression of Sca-1 and myeloid markers in HSPCs. Besides, IFN-I can also upregulate IRFs in a positive feedback manner.	(55, 56, 67–69)
Mouse; Zebrafish	Homeostasis; LPS and Pam3CSK4 administration Genotoxic stress (Chemotherapeutic agent [5-FU]); Aging	IL-6 signaling	HSPCs	Proliferation; Myeloid-biased differentiation; Reduced self-renewal	IL-6 signaling may engage the Akt/mTOR and SHP2/STAT3 pathway to modulate HSPC maintenance. Besides, it is a particularly important modulator in mediating rapid myeloid cell recovery during chemotherapy-induced neutropenia.	(48, 70, 71),
Mouse	Transplantation; Inflammation	TNF signaling	HSCs	Reduced clonal growth and self-renewal	TNF can strongly inhibit the clonal growth and compromise the repopulation capacity of HSPCs that engages its two distinct receptors.	(72)
Human; Mouse	Infection; Inflammation	NF-κB	HSPCs	Reduced necroptosis	NF-κB can induce the transcriptional activation of cIAP2, which can inhibit RIPK3/MLKL-mediated necroptosis.	(62)
Human; Mouse	Infection; DNA introduction; pI:C administration	IFN-I signaling	HSCs	Inhibited proliferation; Apoptosis; Necroptosis	Chronic IFN-I signaling may inhibit HSC proliferation and trigger p53 and RIPK1-CASP8 pathway-mediated apoptosis, or RIPK3- and MLKL-mediated necroptosis of HSCs.	(36, 73, 74),
Mouse	pI:C administration	IFN-I signaling	HSCs	DNA damage	IFN-I signaling induces mitochondrial ROS overproduction and causes DNA damage in HSCs.	(46)