Division of Regenerative Medicine, Stem Cells and Gene Therapy, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, 20132 Milan, Italy.
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15018-23. doi: 10.1073/pnas.1205858109. Epub 2012 Aug 23.
The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.
最近的假设认为，出生前定植于大脑的局部前体细胞可独立于循环单核细胞维持出生后的小胶质细胞，这对治疗各种神经疾病具有重要意义，包括溶酶体贮积症（LSD），对此可应用造血细胞移植（HCT）使表达缺陷功能性水解酶的细胞重新填充受者髓样细胞区室，包括小胶质细胞。通过在 HCT 后不同时间点研究野生型和 LSD 小鼠，我们发现移植造血祖细胞的一部分会短期浸润大脑，这与预处理方案的应用以及脑内疾病状态无关。然而，只有使用能够清除功能上定义的脑驻留髓样前体的调理方案，才能通过早期移民的局部增殖而不是来自循环的成熟细胞的进入来实现小胶质细胞与供体的更替。
