Abstract：
Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
摘要：
越来越多地考虑使用小胶质细胞替代策略来治疗原发性小胶质细胞病，例如具有轴突球体和色素胶质细胞（ALSP）的成人发作性白质脑病。然而,可用的小鼠模型未能概括患者中观察到的各种神经病理学和减少的小胶质细胞数量。在这项研究中,我们产生了一个在Csf1r中缺乏fms-内含子调节元件（FIRE）增强子的异种耐受小鼠模型，发展几乎所有与ALSP相关的标志性病理。值得注意的是,人诱导多能干细胞（iPSC）衍生的小胶质细胞（iMG）祖细胞的移植可恢复稳态小胶质细胞特征，并防止轴突球体的发育，白质异常，反应性星形细胞增多症，脑钙化.此外，CRISPR校正的ALSP患者来源的iMG的移植逆转了先前存在的球体，星形胶质增生,和钙化病理。连同Munro及其同事的伴随研究，我们的结果证明了FIRE小鼠用于ALSP模型的实用性,并提供了令人信服的证据,证明iMG移植可以为ALSP和其他小胶质细胞相关的神经系统疾病提供有前景的新治疗策略.
