在人造血干细胞衍生的器官组织中模拟血脑屏障的形成和脑海绵畸形

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-05-15 DOI:10.1016/j.stem.2024.04.019
Lan Dao, Zhen You, Lu Lu, Tianyang Xu, Avijite Kumer Sarkar, Hui Zhu, Miao Liu, Riccardo Calandrelli, George Yoshida, Pei Lin, Yifei Miao, Sarah Mierke, Srijan Kalva, Haining Zhu, Mingxia Gu, Sudhakar Vadivelu, Sheng Zhong, L. Frank Huang, Ziyuan Guo
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引用次数: 0

摘要

人体血脑屏障(hBBB)是一种高度特化的结构,可调节血液和中枢神经系统(CNS)之间的通道。尽管血脑屏障具有重要的生理作用,但目前还没有可靠的体外模型可以模拟血脑屏障的发育和功能。在这里,我们利用从人类多能干细胞中提取的脑和血管器官组织构建了hBBB组装体。我们验证了血脑屏障(BBB)特异性分子、细胞、转录组和功能特征的获得,并在hBBB组装体中发现了具有空间模式的广泛神经-血管串联。当我们使用源自患者的 hBBB 组合体来模拟脑海绵畸形(CCMs)时,我们发现这些组合体再现了在患者身上观察到的海绵瘤解剖结构和 BBB 破坏。通过比较患者来源的 hBBB 组合体与原发性人类海绵状瘤组织之间的表型和转录组,我们发现了与海绵状瘤相关的分子和细胞改变。总之,我们报告的 hBBB 组合体模拟了 hBBB 的核心特性,并确定了 CCM 的潜在根本原因。
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Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.

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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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