Stem cell-based modeling and single-cell multiomics reveal gene-regulatory mechanisms underlying human skeletal development
Stem cell-based modeling and single-cell multiomics reveal gene-regulatory mechanisms underlying human skeletal development
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DOI：
10.1016/j.celrep.2023.112276
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发表时间：
2023-04-25
期刊：
影响因子：
8.8
通讯作者：
Hojo，Hironori
中科院分区：
文献类型：
--
作者：
Tani，Shoichiro;Okada，Hiroyuki;Hojo，Hironori
虽然骨骼对于运动、内分泌功能和造血是必不可少的，但人类骨骼发育的分子机制仍有待阐明。在这里，我们介绍了一种综合的方法来模拟人类骨骼发育，通过结合体外诱导人类多能干细胞和体内软骨内骨形成，通过植入免疫缺陷小鼠的肾包膜下的硬化器。组织学和scRNA-seq分析表明，诱导的骨重演了软骨内骨化，并由人骨骼细胞和小鼠循环细胞组成。骨骼细胞的类型及其运动轨迹与人类胚胎相似。单细胞多组分析揭示了与构成细胞类型特异性基因调控网络（GRNs）的多个转录因子相关的染色质可及性的动态变化。我们进一步鉴定了ZEB 2，它可能在人类骨生成中调节GRNs。总的来说，这些结果确定了人类骨骼发育中GRNs的组成部分，并为其研究提供了一个有价值的模型。
Although the skeleton is essential for locomotion, endocrine functions, and hematopoiesis, the molecular mechanisms of human skeletal development remain to be elucidated. Here, we introduce an integrative method to model human skeletal development by combiningin vitrosclerotome induction from human pluripotent stem cells andin vivoendochondral bone formation by implanting the sclerotome beneath the renal capsules of immunodeficient mice. Histological and scRNA-seq analyses reveal that the induced bones recapitulate endochondral ossification and are composed of human skeletal cells and mouse circulatory cells. The skeletal cell types and their trajectories are similar to those of human embryos. Single-cell multiome analysis reveals dynamic changes in chromatin accessibility associated with multiple transcription factors constituting cell-type-specific gene-regulatory networks (GRNs). We further identify ZEB2, which may regulate the GRNs in human osteogenesis. Collectively, these results identify components of GRNs in human skeletal development and provide a valuable model for its investigation.