An unexpected role of IL10 in mesoderm induction and differentiation from pluripotent stem cells: Implications in zebrafish angiogenic sprouting, vascular organoid development, and therapeutic angiogenesis

IF 4.5 3区 生物学 Q2 CELL BIOLOGY
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Abstract

Mesoderm induction is a crucial step for vascular cell specification, vascular development and vasculogenesis. However, the cellular and molecular mechanisms underlying mesoderm induction remain elusive. In the present study, a chemically-defined differentiation protocol was used to induce mesoderm formation and generate functional vascular cells including smooth muscle cells (SMCs) and endothelial cells (ECs) from human induced pluripotent stem cells (hiPSCs). Zebrafish larvae were used to detect an in vivo function of interleukin 10 (IL10) in mesoderm formation and vascular development. A three dimensional approach was used to create hiPSC-derived blood vessel organoid (BVO) and explore a potential impact of IL10 on BVO formation. A murine model hind limb ischemia was applied to investigate a therapeutic potential of hiPSC-derived cells treated with or without IL10 during differentiation. We found that IL10 was significantly and specifically up-regulated during mesoderm stage of vascular differentiation. IL10 addition in mesoderm induction media dramatically increased mesoderm induction and vascular cell generation from hiPSCs, whereas an opposite effect was observed with IL10 inhibition. Mechanistic studies revealed that IL10 promotes mesoderm formation and vascular cell differentiation by activating signal transducer and activator of transcription 3 signal pathway. Functional studies with an in vivo model system confirmed that knockdown of IL10 using morpholino antisense oligonucleotides in zebrafish larvae caused defective mesoderm formation, angiogenic sprouting and vascular development. Additionally, our data also show IL10 promotes blood vessel organoid development and enhances vasculogenesis and angiogenesis. Importantly, we demonstrate that IL10 treatment during mesoderm induction stage enhances blood flow perfusion recovery and increases vasculogenesis and therapeutic angiogenesis after hind limb ischemia. Our data, therefore, demonstrate a regulatory role for IL10 in mesoderm formation from hiPSCs and during zebrafish vascular development, providing novel insights into mesoderm induction and vascular cell specifications.
IL10在中胚层诱导和多能干细胞分化中的意外作用:斑马鱼血管萌发、血管器官发育和治疗性血管生成的意义
中胚层诱导是血管细胞规格化、血管发育和血管生成的关键步骤。然而,中胚层诱导的细胞和分子机制仍然难以捉摸。本研究采用化学定义的分化方案诱导中胚层形成,并从人类诱导多能干细胞(hiPSCs)中生成包括平滑肌细胞(SMCs)和内皮细胞(ECs)在内的功能性血管细胞。斑马鱼幼体被用来检测白细胞介素10(IL10)在体内中胚层形成和血管发育中的功能。研究人员采用三维方法创建了源自 hiPSC 的血管器官(BVO),并探索了 IL10 对 BVO 形成的潜在影响。应用小鼠后肢缺血模型研究了分化过程中用或不用IL10处理hiPSC衍生细胞的治疗潜力。我们发现,在血管分化的中胚层阶段,IL10明显且特异性地上调。在中胚层诱导培养基中添加IL10可显著增加中胚层诱导和hiPSCs血管细胞的生成,而抑制IL10则会产生相反的效果。机理研究发现,IL10通过激活信号转导子和转录激活子3信号通路促进中胚层形成和血管细胞分化。体内模型系统的功能研究证实,在斑马鱼幼体中使用吗啉诺反义寡核苷酸敲除IL10会导致中胚层形成、血管萌发和血管发育缺陷。此外,我们的数据还显示,IL10 能促进血管器官发育,增强血管生成和血管形成。重要的是,我们证明了在中胚层诱导阶段处理 IL10 能增强后肢缺血后的血流灌注恢复,增加血管生成和治疗性血管生成。因此,我们的数据证明了IL10在hiPSCs中胚层形成和斑马鱼血管发育过程中的调控作用,为中胚层诱导和血管细胞规格提供了新的见解。
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来源期刊
European journal of cell biology
European journal of cell biology 生物-细胞生物学
CiteScore
7.30
自引率
1.50%
发文量
80
审稿时长
38 days
期刊介绍: The European Journal of Cell Biology, a journal of experimental cell investigation, publishes reviews, original articles and short communications on the structure, function and macromolecular organization of cells and cell components. Contributions focusing on cellular dynamics, motility and differentiation, particularly if related to cellular biochemistry, molecular biology, immunology, neurobiology, and developmental biology are encouraged. Manuscripts describing significant technical advances are also welcome. In addition, papers dealing with biomedical issues of general interest to cell biologists will be published. Contributions addressing cell biological problems in prokaryotes and plants are also welcome.
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