Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
Biochem Biophys Res Commun. 2013 Dec 13;442(3-4):234-41. doi: 10.1016/j.bbrc.2013.11.020. Epub 2013 Nov 15.
Adult hematopoiesis requires tightly regulated cell-cell interactions between hematopoietic cells and the bone marrow stromal microenvironment. We addressed the question if the ectodomain sheddase ADAM10 is essential to regulate adult hematopoiesis. Induced ADAM10 deletion in hematopoietic cells resulted in morphological and histological abnormalities that resemble an unclassified myeloproliferative disorder (MPD). The MPD was characterized by an expansion of granulocytic subpopulations and their infiltration of peripheral hematopoietic tissues, the development of hepatosplenomegaly with extramedullary erythropoiesis, lymphnodepathy and death of the mice around 20weeks after induction. ADAM10 expression analysis during the different stages of the MPD revealed that non-targeted hematopoietic cells repopulated the immune system of the ADAM10-deficient mice. Examination of mice with a myeloid- or epidermis-specific deletion of ADAM10 and bone marrow transplantation (BMT) experiments indicated that the development of the MPD can be triggered by non-cell autonomous effects. We found that plasma levels of clinical markers for MPD such as G-CSF, TIMP-1 and IL-16 were significantly elevated in ADAM10-deficient mice. Our findings indicate that a tightly controlled ADAM10 expression is needed to balance hematopoietic cell-fate decisions in adult mice.
成人造血需要造血细胞与骨髓基质微环境之间严格调控的细胞间相互作用。我们研究了外切酶 ADAM10 是否对调节成人造血至关重要的问题。在造血细胞中诱导 ADAM10 缺失会导致形态和组织学异常，类似于未分类的骨髓增生性疾病 (MPD)。MPD 的特征是粒细胞亚群的扩增及其对周围造血组织的浸润，肝脾肿大以及骨髓外红细胞生成，淋巴结病和大约在诱导后 20 周时小鼠的死亡。在 MPD 的不同阶段进行的 ADAM10 表达分析表明，非靶向造血细胞重新填充了 ADAM10 缺陷小鼠的免疫系统。对具有髓系或表皮特异性 ADAM10 缺失的小鼠和骨髓移植 (BMT) 实验的检查表明，MPD 的发展可以通过非细胞自主效应触发。我们发现，ADAM10 缺陷小鼠的血浆中 MPD 的临床标志物如 G-CSF、TIMP-1 和 IL-16 的水平显著升高。我们的研究结果表明，在成年小鼠中需要严格控制 ADAM10 的表达以平衡造血细胞命运决定。
