利用人诱导多能干细胞来源的小胶质细胞在中枢神经系统中广泛递送疾病修饰蛋白。
Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins.
作者信息
Chadarevian Jean Paul, Davtyan Hayk, Chadarevian Alina L, Nguyen Jasmine, Capocchi Joia K, Le Lauren, Escobar Adrian, Chadarevian Talar, Mansour Kimiya, Deynega Ekaterina, Mgerian Michael, Tu Christina, Kiani Shabestari Sepideh, Carlen-Jones William, Eskandari-Sedighi Ghazaleh, Hasselmann Jonathan, Spitale Robert C, Blurton-Jones Mathew
机构信息
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
出版信息
Cell Stem Cell. 2025 Jun 5;32(6):914-934.e8. doi: 10.1016/j.stem.2025.03.009. Epub 2025 Apr 14.
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.
向大脑广泛递送治疗性蛋白质仍然具有挑战性。为了确定人诱导多能干细胞（iPSC）来源的小胶质细胞（iMG）是否能够实现全脑范围且对病理变化有反应的治疗性物质递送，我们利用CRISPR基因编辑技术对iMG进行工程改造，使其在斑块反应性启动子CD9的控制下表达降解Aβ的酶——中性内肽酶。为了进一步确定增加移植是否能提高疗效，我们采用了一种对集落刺激因子1受体（CSF1R）抑制剂有抗性的方法。有趣的是，在阿尔茨海默病（AD）小鼠中，局部和全脑范围的移植都降低了多种病理生化指标。然而，在斑块密集的海马下托中，只有在广泛的小胶质细胞移植后，斑块负荷、营养不良性神经突、星形胶质细胞增生才有所减少，并且神经元密度得以保留。最后，我们研究了乳腺癌脑转移和脱髓鞘的嵌合模型，证明iMG对不同的神经病理变化会产生不同的转录反应，这可用于实现向中枢神经系统广泛且对病理变化有反应的治疗性物质递送。
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