Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
Neuron. 2024 Aug 21;112(16):2686-2707.e8. doi: 10.1016/j.neuron.2024.05.023. Epub 2024 Jun 18.
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.
小胶质细胞替代策略越来越多地被考虑用于治疗原发性小胶质细胞疾病，如成人发病的伴有轴突球体和色素性神经胶质的脑白质病（ALSP）。然而，现有的小鼠模型未能重现患者中观察到的多种神经病理学和小胶质细胞数量减少。在这项研究中，我们生成了一种缺乏 Csf1r 内 fms 内含子调节元件（FIRE）增强子的异种耐受小鼠模型，该模型几乎发展出与 ALSP 相关的所有标志性病理学。值得注意的是，人诱导多能干细胞（iPSC）衍生的小胶质细胞（iMG）祖细胞的移植恢复了一种稳态小胶质细胞特征，并防止了轴突球体、白质异常、反应性星形胶质细胞增生和脑钙化的发展。此外，CRISPR 校正的 ALSP 患者来源的 iMG 移植可逆转先前存在的球体、星形胶质细胞增生和钙化病理学。与 Munro 及其同事的伴随研究一起，我们的结果证明了 FIRE 小鼠在模拟 ALSP 中的实用性，并提供了令人信服的证据，即 iMG 移植可能为 ALSP 及其他可能与小胶质细胞相关的神经退行性疾病提供一种有前途的新治疗策略。
