Epigenetic adaptation drives monocyte differentiation into microglia-like cells upon engraftment into the retina

Jie Liu, Fengyang Lei, Bin Yan, Naiwen Cui, Jyoti Sharma, Victor Correa, Lara Roach, Savvas Kikolaou, Kristen Pitts, James Chodosh, Daniel E Maidana, Demetrios G Vavvas, Huidan Zhang, David Weitz, Raul Mostoslavsky, Eleftherios I Paschalis
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Abstract

The identification of specific markers for microglia has been a long-standing challenge. Recently, markers such as P2ry12, TMEM119, and Fcrls have been proposed as microglia-specific and widely used to explore microglial functions within various central nervous system (CNS) contexts. The specificity of these markers was based on the assumption that circulating monocytes retain their distinct signatures even after infiltrating the CNS. However, recent findings reveal that infiltrating monocytes can adopt microglia-like characteristics while maintaining a pro-inflammatory profile upon permanent engraftment in the CNS.In this study, we utilize bone marrow chimeras, single-cell RNA sequencing, ATAC-seq, flow cytometry, and immunohistochemistry to demonstrate that engrafted monocytes acquire expression of established microglia markers P2ry12, TMEM119, Fcrls and the pan-myeloid marker Iba1, which has been commonly mischaracterized as microglia-specific. These changes are accompanied by alterations in chromatin accessibility and shifts in chromatin binding motifs that are indicative of microglial identity. Moreover, we show that engrafted monocytes dynamically regulate the expression of CX3CR1, CCR2, Ly6C, and transcription factors PU.1, CTCF, RUNX, AP-1, CEBP, and IRF2, all of which are crucial for shaping microglial identity. This study is the first to illustrate that engrafted monocytes in the retina undergo both epigenetic and transcriptional changes, enabling them to express microglia-like signatures. These findings highlight the need for future research to account for these changes when assessing the roles of monocytes and microglia in CNS pathology.
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表观遗传适应促使单核细胞移植到视网膜后分化成小胶质细胞样细胞
鉴定小胶质细胞的特异性标记物是一项长期的挑战。最近,P2ry12、TMEM119 和 Fcrls 等标记物被认为是小胶质细胞的特异性标记物,并被广泛用于探索小胶质细胞在各种中枢神经系统(CNS)环境中的功能。这些标记物的特异性是基于循环单核细胞在浸润中枢神经系统后仍能保持其独特特征的假设。然而,最近的研究结果表明,浸润的单核细胞在中枢神经系统中永久性移植后,可具有小胶质细胞样特征,同时保持促炎特征。在这项研究中,我们利用骨髓嵌合体、单细胞 RNA 测序、ATAC-seq、流式细胞术和免疫组化技术证明,浸润的单核细胞可表达已确定的小胶质细胞标记物 P2ry12、TMEM119、Fcrls 和泛骨髓标记物 Iba1,而 Iba1 通常被误认为是小胶质细胞特异性标记物。这些变化伴随着染色质可及性的改变和染色质结合基序的转变,而染色质结合基序表明了小胶质细胞的特征。此外,我们还发现移植的单核细胞能动态调节 CX3CR1、CCR2、Ly6C 以及转录因子 PU.1、CTCF、RUNX、AP-1、CEBP 和 IRF2 的表达,所有这些因子对塑造小胶质细胞的特征都至关重要。这项研究首次说明了视网膜中移植的单核细胞经历了表观遗传和转录的变化,使它们能够表达类似小胶质细胞的特征。这些发现强调了未来研究的必要性,即在评估单核细胞和小胶质细胞在中枢神经系统病理学中的作用时要考虑到这些变化。
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