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Acute intestinal inflammation depletes/recruits histamine-expressing myeloid cells from the bone marrow leading to exhaustion of MB-HSCs

Fu, N;Wu, F;Jiang, Z;Kim, W;Ruan, T;Malagola, E;Ochiai, Y;NĂ¡poles, OC;Valenti, G;White, RA;Belin, BR;Zamechek, LB;LaBella, JS;Wang, TC;

Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS) – induced acute colitis has not been addressed. We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-GFP male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon were also analyzed by flow cytometry and immunofluorescence staining. Knockout of HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-CreERT; DTR mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival. In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in a profound HSC exhaustion, accompanied with infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2R agonist, ameliorate the depletion of MB-HSCs and resulted in a significant increased survival of HDC-GFP mice with acute colitis. Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2R agonist significantly enhances survival, suggesting the potential for therapeutic utility.