美国辛辛那提儿童医院Ziyuan Guo、梅奥诊所医学院L. Frank Huang和加州大学Sheng Zhong小组合作在研究中取得进展。他们利用人造血干细胞衍生器官组织模拟了血脑屏障（hBBB）的形成和脑海绵状畸形（CCMs）。该研究于2024年5月15日发表于国际学术期刊《细胞-干细胞》杂志。

据悉，人体血脑屏障是一种高度特化的结构，是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来模拟血脑屏障的发育和功能。

研究人员利用从人多能干细胞中提取的脑和血管器官组织构建了hBBB组装体。研究人员验证了血脑屏障特异性分子、细胞、转录组和功能特征的产生机制，并在hBBB组装体中发现了具有空间模式的泛神经-血管串联。当使用患者来源hBBB组合体来模拟脑海绵状畸形时，研究发现这些组合体再现了从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组合体与原发性人海绵状瘤组织之间的表型和转录组，研究发现了与海绵状瘤相关的分子和细胞改变。总之，该研究生成的hBBB组合体模拟了hBBB的核心特性，并确定了CCM产生的潜在根本原因。

附：英文原文

Title: Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids

Author: 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

Issue&Volume: 2024-05-15

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

DOI: 10.1016/j.stem.2024.04.019

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00146-2