斯坦福大学医学院Marius Wernig小组近日取得一项新成果。经过不懈努力，他们的研究开发出了通过异基因脑小胶质细胞替代治疗性基因恢复。2025年8月6日出版的《自然》杂志发表了这项成果。

在这里，该研究团队报告了一种不需要清髓预处理的脑受限、高效的小胶质细胞替代方法。与先前的假设不同，该团队发现造血干细胞不需要重新填充脑环境的髓细胞室。相反，在脑内注射后，具有Sca1的祖细胞可以高效地替代小胶质细胞。这一发现促进了脑限制性预适应的发展，避免了长期的外周移植，从而消除了诸如移植物抗宿主病等并发症。评估其治疗潜力，该课题组研究人员发现他们的同种异体小胶质细胞替代方法拯救了Sandhoff病的小鼠模型，Sandhoff病是一种由己糖氨基酶B缺乏症引起的溶酶体贮存病。为了支持这种方法的翻译相关性，小组发现人类诱导多能干细胞衍生的髓系祖细胞在脑限制条件下显示出类似的植入潜力。他们的结果克服了目前传统HCT的局限性，并可能为大脑同种异体小胶质细胞疗法的发展铺平道路。

研究人员表示，全身造血干细胞和祖细胞移植（HCT）后移植的异基因骨髓细胞迁移到大脑中，作为纠正大脑遗传缺陷（如溶酶体贮积病）的治疗方式，具有很大的前景。然而，同种异体HCT所需的毒性骨髓消融可能会导致严重的危及生命的副作用，限制了其适用性。此外，移植的异基因骨髓细胞即使在像大脑这样具有免疫特权的器官中也极易受到排斥。

附：英文原文

Title: Therapeutic genetic restoration through allogeneic brain microglia replacement

Author: Mader, Marius Marc-Daniel, Scavetti, Alexa, Yoo, Yongjin, Chai, Aaron Tianyue, Uenaka, Takeshi, Wernig, Marius

Issue&Volume: 2025-08-06

Abstract: Migration of transplanted allogeneic myeloid cells into the brain following systemic hematopoietic stem and progenitor cells transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases.1–3 However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Unlike previous assumptions, we found that hematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment. In contrast, Sca1- committed progenitor cells were highly efficient to replace microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment thus eliminating complications such as graft-vs-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescues the murine model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human induced pluripotent stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.

DOI: 10.1038/s41586-025-09461-6

Source: https://www.nature.com/articles/s41586-025-09461-6