Mader Marius Marc-Daniel, Scavetti Alexa, Yoo Yongjin, Chai Aaron Tianyue, Uenaka Takeshi, Wernig Marius
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09461-6.
Migration of transplanted allogeneic myeloid cells into the brain following systemic haematopoietic stem and progenitor cell transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases. 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. Contrary to previous assumptions, we found that haematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment, and Sca1 committed progenitor cells were highly efficient in replacing 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-versus-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescued the mouse 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 embryonic 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.
在全身造血干细胞和祖细胞移植（HCT）后，移植的同种异体髓系细胞迁移至脑内，作为一种纠正脑内遗传缺陷（如溶酶体贮积病）的治疗方式具有巨大潜力。然而，同种异体HCT所需的毒性清髓可能会导致严重的、危及生命的副作用，限制了其应用。此外，即使在像脑这样的免疫特惠器官中，移植的同种异体髓系细胞也极易被排斥。在此，我们报告一种无需清髓预处理的脑限制性、高效小胶质细胞替代方法。与先前的假设相反，我们发现重新填充脑环境中的髓系区室并不需要造血干细胞，并且在脑内注射后，Sca1定向祖细胞在替代小胶质细胞方面效率极高。这一发现促成了脑限制性预处理的发展，并避免了长期的外周植入，从而消除了诸如移植物抗宿主病等并发症。在评估其治疗潜力时，我们发现我们的同种异体小胶质细胞替代方法挽救了Sandhoff病小鼠模型，这是一种由己糖胺酶B缺乏引起的溶酶体贮积病。为支持这种方法的转化相关性，我们发现人胚胎干细胞来源的髓系祖细胞在脑限制性预处理后表现出类似的植入潜力。我们的结果克服了传统HCT的当前局限性，并可能为脑同种异体小胶质细胞疗法的发展铺平道路。
