Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS.
Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS.
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DOI：
10.1186/s12974-020-01931-0
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发表时间：
2020-09-20
影响因子：
9.3
通讯作者：
Green KN
中科院分区：
文献类型：
--
作者：
Hohsfield LA;Najafi AR;Ghorbanian Y;Soni N;Hingco EE;Kim SJ;Jue AD;Swarup V;Inlay MA;Green KN
小胶质细胞是大脑的主要常驻髓样细胞，通过维持组织稳态和对损伤或疾病作出反应，在免疫防御中发挥关键作用。然而，小胶质细胞的激活和功能障碍与许多中枢神经系统（CNS）疾病有关，因此开发工具来操纵和替代中枢神经系统中的这些髓样细胞具有治疗意义。通过全身照射、骨髓移植和集落刺激因子1受体抑制，我们实现了外周骨髓来源的髓样细胞（即单核细胞）在脑实质中的长期和全脑（~ 80%）植入和定植，并评估了它们在中枢神经系统中定植的长期影响。在这里，我们发现了一个单核细胞信号，包括Ccr1、Ms4a6b、Ms4a6c、Ms4a7、Apobec1、Lyz2、Mrc1、Tmem221、Tlr8、Lilrb4a、Msr1、Nnt和Wdfy1的上调，以及Siglech、Slc2a5和Ccl21a/b的下调。我们证明，照射和单核细胞长期（~ 6个月）植入中枢神经系统可诱导转录谱、星形胶质细胞、神经元结构（包括突触成分）和认知方面的脑区域依赖性改变。尽管我们的研究结果表明，用外周来源的髓样细胞替代小胶质细胞是可行的，并且用海马中的单核细胞替代小胶质细胞可以逆转辐照诱导的变化，但我们也观察到，全脑范围内的外周髓样细胞移植（依赖于辐照）可能导致认知和突触缺陷。这些发现为更好地理解髓样细胞在大脑中的作用和复杂性提供了见解，包括它们对其他中枢神经系统细胞和功能结果的调节。
Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest. Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.
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DOI：
10.1007/s00109-017-1573-x
发表时间：
2017-11
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Faraco G;Park L;Anrather J;Iadecola C
通讯作者：
Iadecola C
影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
影响因子：
4.6
作者：
Chen SC;Abe Y;Fang PT;Hsieh YJ;Yang YI;Lu TY;Oda S;Mitani H;Lian SL;Tyan YC;Huang CJ;Hisatsune T
通讯作者：
Hisatsune T
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D
辐射引起的脑损伤的分子，细胞和功能效应：综述。
影响因子：
5.6
作者：
Balentova S;Adamkov M
通讯作者：
Adamkov M