Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Transl Med. 2022 Mar 16;14(636):eabl9945. doi: 10.1126/scitranslmed.abl9945.
Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
经清髓性预处理的造血细胞移植已被用于治疗各种遗传代谢综合征，但在影响大脑的疾病中效果不佳，这可能是由于骨髓细胞向中枢神经系统的掺入不良且可变。在这里，我们开发并表征了一种无需对供体或宿主进行基因操作即可实现骨髓细胞对小胶质细胞近乎完全和均匀替代的方法。高嵌合体是由于在小胶质细胞再增殖期间稀有供体细胞的竞争优势所致，而不是来自外周的募集增强所致。造血干细胞，但不是即刻髓样或单核细胞祖细胞，具有与整个骨髓相当的完全小胶质细胞替代能力。为了探索其治疗潜力，我们将小胶质细胞替代应用于 Prosaposin 缺乏症的小鼠模型中，该模型的特征是进行性神经退行性表型。我们发现治疗大脑中的小脑神经退行性变和神经胶质增生减少，运动和平衡障碍改善，甚至在成年早期开始治疗时寿命延长。这项概念验证研究表明，有效的小胶质细胞替代可能对各种神经退行性疾病具有治疗效果。
