美国加州大学Mathew Blurton-Jones课题组的一项最新研究揭示了利用人类iPSC -小胶质细胞在全中枢神经系统范围内传递疾病修饰蛋白。2025年4月14日，国际知名学术期刊《细胞—干细胞》发表了这一成果。

为了确定人类诱导多能干细胞(iPSC)-小胶质细胞（iMG）是否能够实现全脑和病理反应性的治疗药物递送，研究团队利用CRISPR基因编辑技术对iMG进行改造，使其在斑块反应启动子CD9的控制下表达a β-降解酶neprilysin。为了进一步确定植入增加是否能提高疗效，课题组采用了CSF1R抑制剂耐药性方法。有趣的是，阿尔茨海默病（AD）小鼠的局部和全脑植入都降低了多种病理生化指标。

然而，在斑块密集的骨下，斑块负荷的减少、神经突的营养不良、星形胶质增生和神经元密度的保持只有在广泛的小胶质细胞植入后才能实现。最后，该课题组研究人员研究了乳腺癌脑转移和脱髓鞘的嵌合模型，证明iMG对不同的神经病变有不同的转录反应，这可以用于广泛和病理反应性地向中枢神经系统输送治疗药物。

据介绍，将治疗性蛋白质广泛输送到大脑仍然具有挑战性。

附：英文原文

Title: Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

Author: Jean Paul Chadarevian, Hayk Davtyan, Alina L. Chadarevian, Jasmine Nguyen, Joia K. Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C. Spitale, Mathew Blurton-Jones

Issue&Volume: 2025-04-14

Abstract: Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer’s disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.

DOI: 10.1016/j.stem.2025.03.009

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00099-2