Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Hematology, Saiseikai Fukuoka General Hospital, 1-3-46 Tenjin, Chuo-ku, Fukuoka, 810-0001, Japan.
Int J Hematol. 2022 Feb;115(2):198-207. doi: 10.1007/s12185-021-03239-y. Epub 2021 Nov 13.
Primary myelofibrosis (PMF) is a clonal stem cell disorder characterized by myeloid dominant hematopoiesis and dysregulated proliferation of fibroblasts in the bone marrow. However, how these aberrant myeloid cells and fibroblasts are produced remains unclear.
In this study, we examined in vivo engraftment kinetics of PMF patient-derived CD34+ cells in immunecompromised NOD/SCID/IL2rgKO (NSG) mice. Engrafted human cells were analyzed with flow cytometry, and proliferation of fibroblastic cells and bone marrow fibrosis were assessed with the histo-pathological examination.
Transplantation of PMF patient-derived circulating CD34+ fractions into NSG newborns recapitulates clinical features of human PMF. Engraftment of human CD45+ leukocytes resulted in anemia and myeloid hyperplasia accompanied by bone marrow fibrosis by six months post-transplantation. Fibrotic bone marrow contained CD45-vimentin+ cells of both human and mouse origin, suggesting that circulating malignant CD34+ subsets contribute to myelofibrotic changes in PMF through direct and indirect mechanisms.
A patient-derived xenotransplantation (PDX) model of PMF allows in vivo examination of disease onset and propagation originating from immature CD34+ cells and will support the investigation of pathogenesis and development of therapeutic modalities for the disorder.
原发性骨髓纤维化(PMF)是一种克隆性干细胞疾病,其特征是骨髓中髓系优势造血和纤维母细胞的失调增殖。然而,这些异常的髓系细胞和纤维母细胞是如何产生的仍不清楚。
在这项研究中,我们检查了 PMF 患者来源的 CD34+细胞在免疫缺陷 NOD/SCID/IL2rgKO(NSG)小鼠体内的植入动力学。通过流式细胞术分析植入的人类细胞,并通过组织病理学检查评估成纤维细胞的增殖和骨髓纤维化。
将 PMF 患者来源的循环 CD34+ 细胞群移植到 NSG 新生小鼠中,重现了人类 PMF 的临床特征。移植后 6 个月,人 CD45+白细胞的植入导致贫血和髓系增生,并伴有骨髓纤维化。纤维化的骨髓中含有人类和小鼠来源的 CD45-vimentin+细胞,表明循环恶性 CD34+细胞亚群通过直接和间接机制导致 PMF 的骨髓纤维化变化。
PMF 的患者来源异种移植(PDX)模型允许对源自不成熟 CD34+细胞的疾病发病和传播进行体内检查,并将支持对该疾病的发病机制和治疗方法的研究。