Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs

Abstract

Background & Aims 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. Methods We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC–green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC–tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (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. Results In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by 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 H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. Conclusions Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.

Immature myeloid cells are indispensable for intestinal regeneration post irradiation injury

“…The copyright holder for this preprint this version posted March 1, 2023. ; https://doi.org/10.1101/2023.02.28.530500 doi: bioRxiv preprint homeostasis but become more abundant during disease states. These cells are rapidly mobilized in response to inflammatory conditions to fight infection and promote tissue repair, but such mobilization promotes activation of HSCs, which can eventually lead to their exhaustion if such activation is sustained (Fu et al, 2021). Although it was known these cells infiltrate damaged tissues to promote regeneration, their functions therein have been understudied.…”

“…We have previously shown that Hdc + IMCs are mobilized from the bone marrow to the colon during DSS-induced colitis (Fu et al, 2021). To test if Hdc + IMCs are involved in intestinal regeneration, we employed a model of 12 Gy whole-body irradiation (WB-IR), which induces acute damage to the intestinal epithelial stem and progenitor zone cells (Booth et al, 2012).…”

“…Hdc + immature myeloid cells (IMCs) are primarily granulocytic, marked by CD11b + Ly6G + . During homeostasis, these cells comprise ≥80% of IMCs in the bone marrow and are rarely found in the circulation or peripheral tissues (Fu et al, 2021). In addition to maintaining the HSC niche through histamine production, this IMC population is rapidly mobilized from the bone marrow to damaged tissues in response to inflammatory conditions such as acute colitis or LPS endotoxemia, where they contribute to growth and regeneration (Chen et al, 2017; Fu et al, 2021).…”

Bifidobacterium lactis BL-99 protects mice with osteoporosis caused by colitis via gut inflammation and gut microbiota regulation

“…In addition, gut microbes can shape bone metabolism by influencing immune responses and altering relative OCL and OB activity levels via the production of specific metabolites. [10][11][12] Dietary calcium is absorbed into the blood via calcium channels within the small intestinal epithelium and through active transport mechanisms, whereupon it is passively transported throughout the entire gastrointestinal tract. IBD can result in alterations in the composition of the gut microbiota, leading to changes in the secretion of particular shortchain fatty acids as well as changes in the lumenal pH within the intestines, thereby impairing calcium absorption and resulting in dysregulated bone metabolism that can further progress to cause osteoporosis.…”

Is Avoiding Stem Cell Exhaustion the New Therapeutic Approach in Colitis?

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology, Fu et al 6 from the Wang laboratory sought to explore the role of HDC-expressing myeloid cells and MB-HSCs in the setting of acute colitis by using the dextran sulfate sodium (DSS)-induced intestinal injury model of inflammatory bowel disease. Although the mechanism by which DSS induces intestinal inflammation is not entirely clear, it is likely the result of epithelial damage of the lining of the large intestine that allows infiltration of proinflammatory luminal contents such as bacteria and their products into underlying mucosa and subsequent activation of the innate immune system.…”