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Exposure of patient-derived mesenchymal stromal cells to TGFB1 supports fibrosis induction in a pediatric acute megakaryoblastic leukemia model
Molecular Cancer Research ( IF 4.1 ) Pub Date : 2020-07-08 , DOI: 10.1158/1541-7786.mcr-20-0091
Theresa Hack 1 , Stefanie Bertram 2 , Helen Blair 3 , Verena Börger 4 , Guntram Büsche 5 , Lora Denson 1 , Enrico Fruth 1 , Bernd Giebel 4 , Olaf Heidenreich 3, 6 , Ludger Klein-Hitpass 7 , Laxmikanth Kollipara 8 , Stephanie Sendker 1 , Albert Sickmann 8, 9, 10 , Christiane Walter 1 , Nils von Neuhoff 1 , Helmut Hanenberg 1, 11 , Dirk Reinhardt 1 , Markus Schneider 1 , Mareike Rasche 1
Affiliation  

Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSC) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche (BMN). To model the BMN of pediatric patients with AMKL in mice, we first established MSCs from pediatric patients with AMKL (n = 5) and ML-DS (n = 9). Healthy donor control MSCs (n = 6) were generated from unaffected children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential and enrichment of proliferation-associated genes. Importantly, TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN subcutaneously in immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice, using a mixture of MSCs, human umbilical vein endothelial cell, and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this BMN after 8 weeks induced fibrosis grade I/II in a dose-dependent fashion over a time period of 4 weeks. Thus, our study developed a humanized mouse model that will be instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL blasts in future. Implications: TGFB1 supports fibrosis induction in a pediatric AMKL model generated with patient-derived MSCs. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg. Visual Overview

中文翻译:


将患者来源的间充质基质细胞暴露于 TGFB1 支持小儿急性巨核细胞白血病模型中纤维化的诱导



骨髓纤维化(BMF)是急性白血病的罕见并发症。在儿科,它主要发生在急性巨核细胞白血病 (AMKL),尤其是 21 三体性患者,称为唐氏综合症髓系白血病 (ML-DS)。间充质基质细胞(MSC)和髓系母细胞特异性释放的细胞因子的缺陷被认为是骨髓生态位(BMN)纤维化的主要驱动因素。为了在小鼠中模拟 AMKL 儿科患者的 BMN,我们首先从 AMKL 儿科患者 (n = 5) 和 ML-DS (n = 9) 中建立 MSC。健康供体对照 MSC(n = 6)是从未受影响的儿童和 ≤18 岁的青少年中产生的。 MSC 的稳态分析显示,源自患者的 MSC 表现出成脂分化潜力降低和增殖相关基因富集。重要的是,体外暴露的 TGFB1 促进了所有三个 MSC 实体的早期促纤维化变化。为了研究更长时间的 BMF 诱导,我们使用 MSC、人脐静脉内皮细胞和 Matrigel 的混合物,在免疫缺陷的 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ 小鼠皮下皮下创建了体内人源化人工 BMN。 8周后将作为TGFB1产生者的AMKL母细胞注射到该BMN中,在4周的时间段内以剂量依赖性方式诱导I/II级纤维化。因此,我们的研究开发了一种人源化小鼠模型,该模型将有助于将来专门检查 AMKL 母细胞的白血病发生和治疗靶点。意义:TGFB1 支持用患者来源的 MSC 生成的儿科 AMKL 模型中的纤维化诱导。视觉概述:http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg。视觉概览
更新日期:2020-07-08
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