A 3-D hydrogel based system for hematopoietic differentiation and its use in modeling down syndrome associated transient myeloproliferative disorder,Biomaterials Science

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A 3-D hydrogel based system for hematopoietic differentiation and its use in modeling down syndrome associated transient myeloproliferative disorder
Biomaterials Science ( IF 5.8 ) Pub Date : 2021-08-04 , DOI: 10.1039/d1bm00442e
Ishnoor Sidhu _{1,

2} , Sonali P Barwe _{1,

2} , Kristi L Kiick ₂ , E Anders Kolb ₁ , Anilkumar Gopalakrishnapillai _{1,

2}

Affiliation

Induced pluripotent stem cells (iPSCs) provide an extraordinary tool for disease modeling owing to their potential to differentiate into the desired cell type. The differentiation of iPSCs is typically performed on 2-dimensional monolayers of stromal cell or animal tissue derived extracellular matrices. Recent advancements in disease modeling have utilized iPSCs in 3-dimensional (3D) cultures to study diseases such as muscular dystrophy, cardiomyopathy, and pulmonary fibrosis. However, these approaches are yet to be explored in modeling the hematological malignancies. Transient myeloproliferative disorder (TMD) is a preleukemic stage, which is induced in 10–20% of children with trisomy 21 possessing the pathognomonic mutation in the transcription factor GATA1. In this study, we established a synthetic 3D iPSC culture system for modeling TMD via hematopoietic differentiation of customized iPSCs. A chemically cross-linkable PEG hydrogel decorated with integrin binding peptide was found to be permissive of hematopoietic differentiation of iPSCs. It provided a cost-effective system for the generation of hematopoietic stem and progenitor cells (HSPCs) with higher yield of early HSPCs compared to traditional 2D culture on Matrigel coated dishes. Characterization of the HSPCs produced from the iPSC lines cultured in 3D showed that the erythroid population was reduced whereas the megakaryoid and myeloid populations were significantly increased in GATA1 mutant trisomic line compared to disomic or trisomic lines with wild-type GATA1, consistent with TMD characteristics. In conclusion, we have identified a cost-effective tunable 3D hydrogel system to model TMD.

中文翻译：

基于 3-D 水凝胶的造血分化系统及其在唐氏综合症相关短暂性骨髓增殖性疾病建模中的应用

诱导多能干细胞（iPSC）由于具有分化成所需细胞类型的潜力，为疾病建模提供了非凡的工具。iPSC 的分化通常在基质细胞或动物组织衍生的细胞外基质的二维单层上进行。疾病建模领域的最新进展已利用 3 维 (3D) 培养物中的 iPSC 来研究肌营养不良症、心肌病和肺纤维化等疾病。然而，这些方法在血液恶性肿瘤建模方面仍有待探索。短暂性骨髓增殖性疾病 (TMD) 属于白血病前期阶段，10-20% 的 21 三体症儿童在转录因子GATA1中具有特征性突变，可诱发该疾病。在这项研究中，我们建立了一个合成的 3D iPSC 培养系统，用于通过定制 iPSC 的造血分化来模拟 TMD。发现用整联蛋白结合肽修饰的化学交联 PEG 水凝胶允许 iPSC 的造血分化。它为造血干细胞和祖细胞 (HSPC) 的生成提供了一种经济高效的系统，与 Matrigel 包被培养皿上的传统 2D 培养相比，早期 HSPC 的产量更高。3D 培养的 iPSC 系产生的 HSPC 的表征表明，与野生型GATA1的二体或三体系相比，GATA1 突变三体系中的红细胞群减少，而巨核细胞和髓系细胞群显着增加，这与 TMD 特征一致。总之，我们已经确定了一种经济高效的可调谐 3D 水凝胶系统来模拟 TMD。

更新日期：2021-08-09

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