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.

中文翻译：

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急性肠道炎症消耗/招募骨髓中表达组胺的骨髓细胞，导致 MB-HSC 耗尽

 背景与目标

组氨酸脱羧酶 (HDC) 是一种组胺合成酶，在髓系细胞亚群中表达，但也标记在髓系需求损伤时被激活的静态髓系造血干细胞 (MB-HSC)。然而，MB-HSC 在葡聚糖硫酸钠 (DSS) 诱导的急性结肠炎中的作用尚未得到解决。

 方法

我们通过在不同时间点用 5% DSS 处理 HDC-绿色荧光蛋白 (GFP) 雄性小鼠，通过流式细胞术研究了急性肠道炎症中的 HDC+ MB-HSC 和骨髓细胞。还通过流式细胞术和免疫荧光染色分析了结肠中的 HDC+ 骨髓细胞。使用HDC-/-敲除HDC基因； HDC-GFP 和使用 HDC-GFP 消融 HDC+ 骨髓细胞； HDC-他莫昔芬诱导重组酶Cre系统；对白喉毒素受体（DTR）小鼠进行了实验。通过用 H2 激动剂二马普利二盐酸盐治疗 DSS 处理的小鼠，研究了 H2 受体信号传导在急性结肠炎中的作用。进行卡普兰-迈耶生存分析以评估对生存的影响。

 结果

在急性结肠炎中，骨髓中的 MB-HSC 的快速激活和扩张在早期就很明显，随后逐渐耗尽，导致 HSC 严重耗竭，同时伴随着 HDC+ 骨髓细胞增加对结肠的浸润。 HDC 基因敲除和 HDC+ 骨髓细胞消融增强了 HDC+ MB-HSC 的早期消耗，而 H2 受体激动剂治疗可改善 MB-HSC 的消耗，并导致患有急性结肠炎的 HDC-GFP 小鼠的存活率显着增加。

 结论

骨髓 MB-HSC 的耗竭有助于 DSS 诱导的急性结肠炎的进展，而 H2 受体激动剂保持 MB-HSC 的静止状态可显着提高生存率，这表明其具有治疗用途的潜力。