In Vitro Recapitulation of Murine Thymopoiesis from Single Hematopoietic Stem Cells,Cell Reports

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In Vitro Recapitulation of Murine Thymopoiesis from Single Hematopoietic Stem Cells
Cell Reports ( IF 7.5 ) Pub Date : 2020-10-27 , DOI: 10.1016/j.celrep.2020.108320
Amélie Montel-Hagen ₁ , Victoria Sun ₂ , David Casero ₁ , Steven Tsai ₃ , Alexandre Zampieri ₁ , Nicholas Jackson ₁ , Suwen Li ₄ , Shawn Lopez ₁ , Yuhua Zhu ₁ , Brent Chick ₁ , Chongbin He ₁ , Stéphanie C de Barros ₁ , Christopher S Seet ₅ , Gay M Crooks ₆

Affiliation

Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.

We report a serum-free, 3D murine artificial thymic organoid (M-ATO) system that mimics normal murine thymopoiesis with the production of all T cell stages, from early thymic progenitors to functional single-positive (CD8SP and CD4SP) TCRαβ and TCRγδ cells. RNA sequencing aligns M-ATO-derived populations with phenotypically identical primary thymocytes. M-ATOs initiated with Rag1^−/− marrow produce the same differentiation block as seen in the endogenous thymus, and Notch signaling patterns in M-ATOs mirror primary thymopoiesis. M-ATOs initiated with defined hematopoietic stem cells (HSCs) and lymphoid progenitors from marrow and thymus generate each of the downstream differentiation stages, allowing the kinetics of T cell differentiation to be tracked. Remarkably, single HSCs deposited into each M-ATO generate the complete trajectory of T cell differentiation, producing diverse TCR repertoires across clones that largely match endogenous thymus. M-ATOs represent a highly reproducible and efficient experimental platform for the interrogation of clonal thymopoiesis from HSCs.

中文翻译：

小鼠单造血干细胞胸腺生成的体外重现

我们报道了一种无血清、3D 鼠类人工胸腺类器官 (M-ATO) 系统，该系统模仿正常鼠类胸腺生成，可产生所有阶段的 T 细胞，从早期胸腺祖细胞到功能性单阳性（CD8SP 和 CD4SP）TCRαβ 和 TCRγδ 细胞。 RNA 测序将 M-ATO 衍生群体与表型相同的初级胸腺细胞进行比对。由Rag1 ^−/−骨髓启动的 M-ATO 产生与内源性胸腺相同的分化块，并且 M-ATO 中的 Notch 信号传导模式反映了初级胸腺生成。由特定的造血干细胞 (HSC) 以及来自骨髓和胸腺的淋巴祖细胞启动的 M-ATO 产生每个下游分化阶段，从而可以跟踪 T 细胞分化的动力学。值得注意的是，沉积到每个 M-ATO 中的单个 HSC 生成 T 细胞分化的完整轨迹，在克隆中产生与内源胸腺基本匹配的多样化 TCR 库。 M-ATO 代表了一个高度可重复且高效的实验平台，用于研究 HSC 的克隆胸腺生成作用。

更新日期：2020-10-30

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