Apoptotic extracellular vesicles carrying Mif regulate macrophage recruitment and compensatory proliferation in neighboring epithelial stem cells during tissue maintenance.

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
PLoS Biology Pub Date : 2024-11-04 eCollection Date: 2024-11-01 DOI:10.1371/journal.pbio.3002194
Safia A Essien, Ivanshi Ahuja, George T Eisenhoffer
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引用次数: 0

Abstract

Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss to maintain tissue homeostasis. While apoptotic cell-derived extracellular vesicles (AEVs) can transmit instructional cues to mediate communication with neighboring cells, the molecular mechanisms that induce cell division are not well understood. Here, we show that macrophage migration inhibitory factor (Mif)-containing AEVs regulate compensatory proliferation via ERK signaling in epithelial stem cells of larval zebrafish. Time-lapse imaging showed efferocytosis of AEVs from dying epithelial stem cells by healthy neighboring stem cells. Proteomic and ultrastructure analysis of purified AEVs identified Mif localization on the AEV surface. Pharmacological inhibition or genetic mutation of Mif, or its cognate receptor CD74, decreased levels of phosphorylated ERK and compensatory proliferation in the neighboring epithelial stem cells. Disruption of Mif activity also caused decreased numbers of macrophages patrolling near AEVs, while depletion of the macrophage lineage resulted in a reduced proliferative response by the epithelial stem cells. We propose that AEVs carrying Mif directly stimulate epithelial stem cell repopulation and guide macrophages to cell non-autonomously induce localized proliferation to sustain overall cell numbers during tissue maintenance.

在组织维持过程中,携带 Mif 的凋亡细胞外囊泡可调节巨噬细胞的招募和邻近上皮干细胞的代偿性增殖。
凋亡细胞可向邻近细胞发出信号,以刺激细胞增殖并补偿细胞损失,从而维持组织的平衡。虽然凋亡细胞衍生的细胞外囊泡(AEVs)可以传递指令线索,介导与邻近细胞的交流,但诱导细胞分裂的分子机制还不十分清楚。在这里,我们发现含巨噬细胞迁移抑制因子(Mif)的AEV通过ERK信号调节幼体斑马鱼上皮干细胞的代偿性增殖。延时成像显示,健康的邻近干细胞会从濒死的上皮干细胞中排出AEVs。对纯化的AEV进行的蛋白质组学和超微结构分析确定了Mif在AEV表面的定位。药理抑制或基因突变Mif或其同源受体CD74,可降低磷酸化ERK的水平,并减少邻近上皮干细胞的代偿性增殖。Mif活性的破坏还导致在AEV附近巡逻的巨噬细胞数量减少,而巨噬细胞系的耗竭导致上皮干细胞的增殖反应减弱。我们认为,携带Mif的AEV可直接刺激上皮干细胞的重新填充,并引导巨噬细胞非自主地诱导局部增殖,以维持组织维持过程中的整体细胞数量。
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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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