Migrasomes trigger innate immune activation and mediate transmission of senescence signals across human cells

Abstract

Aging is a complex and heterogeneous process, raising important questions about how aging is differently impacted by underlying genetics and external factors. Recently, migrasomes, newly discovered organelles, have been identified to play important roles in various physiological and pathological processes by facilitating cell-to-cell communication. Thus far, their involvement in cellular senescence and aging remains largely unexplored. In this study, we aimed to investigate how migrasomes impact on cellular aging by leveraging multiple cellular senescence models, including replicatively senescent (RS), pathologically senescent and stress-induced senescent human mesenchymal stem cells (hMSCs), as well as RS human primary fibroblasts. In all cellular aging models, we detected an enhanced formation of migrasomes. Notably, migrasomes in senescent cells exhibited an accumulation of numerous aging hallmarks, such as dysfunctional mitochondria, endogenous retroviruses, and senescence-associated pro-inflammatory cytokines. Furthermore, we discovered that migrasomes derived from senescent cells can be taken up by young cells, thereby transferring aging signals and subsequently causing premature senescence phenotypes in recipient cells. Mechanistically, we found that treatment with migrasomes derived from senescent cells activated the innate immune response. Thus, our study sheds light on a pivotal role of migrasomes in mediating the contagiousness of aging.

Keywords

migrasomes / cellular senescence / endogenous retrovirus / senescence-associated secretory phenotype / aging

References

[1] Aging Biomarker Consortium; Bao H, Cao J, Chen M, et al. Biomarkers of aging. Sci China Life Sci 2023;66:893–1066.

[2] Guo J, Huang X, Dou L, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 2022;7:391.

[3] Cai Y, Song W, Li J, et al. The landscape of aging. Sci China Life Sci 2022;65:2354–454.

[4] Aging Biomarker Consortium, Jia Y-J, Yu-Juan Jia, et al. A framework of biomarkers for brain aging: a consensus statement by the Aging Biomarker Consortium. Life Med 2023;2:lnad017.

[5] Cai Y, Ji Z, Wang S, et al. Genetic enhancement: an avenue to combat aging-related diseases. Life Med 2022;1:307–18.

[6] Lopez-Otin C, Blasco MA, Partridge L, et al. Hallmarks of aging: An expanding universe. Cell 2023;186:243–78.

[7] Vu R, Jin S, Sun P, et al. Wound healing in aged skin exhibits systems-level alterations in cellular composition and cell-cell communication. Cell Rep 2022;40:111155.

[8] Ma S, Wang S, Ye Y, et al. Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues. Cell Stem Cell 2022;29:990–1005.e10.

[9] Liu X, Liu Z, Wu Z, et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 2023;186:287–304.e26.

[10] Zhang H, Li J, Yu Y, et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell Rep 2023;42:112593.

[11] Rando TA, Wyss-Coray T. Asynchronous, contagious and digital aging. Nat Aging 2021;1:29–35.

[12] Ma L, Li Y, Peng J, et al. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res 2015;25:24–38.

[13] Yu S, Yu L. Migrasome biogenesis and functions. FEBS J 2022;289:7246–54.

[14] Jiang D, Li Y, Yu L. Detection, purification, characterization, and manipulation of migrasomes. Curr Protoc 2023;3:e856.

[15] Dharan R, Huang Y, Cheppali SK, et al. Tetraspanin 4 stabilizes membrane swellings and facilitates their maturation into migrasomes. Nat Commun 2023;14:1037.

[16] Dharan R, Goren S, Cheppali SK, et al. Transmembrane proteins tetraspanin 4 and CD9 sense membrane curvature. Proc Natl Acad Sci USA 2022;119:e2208993119.

[17] Fan C, Shi X, Zhao K, et al. Cell migration orchestrates migrasome formation by shaping retraction fibers. J Cell Biol 2022;221:e202109168.

[18] Zhu M, Zou Q, Huang R, et al. Lateral transfer of mRNA and protein by migrasomes modifies the recipient cells. Cell Res 2021;31:237–40.

[19] Zhao X, Lei Y, Zheng J, et al. Identification of markers for migrasome detection. Cell Discov 2019;5:27.

[20] Zhang C, Li T, Yin S, et al. Monocytes deposit migrasomes to promote embryonic angiogenesis. Nat Cell Biol 2022;24:1726–38.

[21] Jiang D, Jiang Z, Lu D, et al. Migrasomes provide regional cues for organ morphogenesis during zebrafish gastrulation. Nat Cell Biol 2019;21:966–77.

[22] Qin Y, Yang J, Liang C, et al. Pan-cancer analysis identifies migrasome-related genes as a potential immunotherapeutic target: A bulk omics research and single cell sequencing validation. Front Immunol 2022;13:994828.

[23] Hu M, Li T, Ma X, et al. Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model. Nat Commun 2023;14:3945.

[24] Zheng Y, Lang Y, Qi B, et al. TSPAN4 and migrasomes in atherosclerosis regression correlated to myocardial infarction and pan-cancer progression. Cell Adh Migr 2023;17:14–9.

[25] Wu L, Yang S, Li H, et al. TSPAN4-positive migrasome derived from retinal pigmented epithelium cells contributes to the development of proliferative vitreoretinopathy. J Nanobiotechnol 2022;20:519.

[26] Wu Z, Zhang W, Song M, et al. Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome. Protein Cell 2018;9:333–50.

[27] Chen Y, Li Y, Ma L, et al. Detection of migrasomes. Methods Mol Biol 2018;1749:43–9.

[28] Deniz IA, Karbanová J, Wobus M, et al. Mesenchymal stromal cell-associated migrasomes: a new source of chemoattractant for cells of hematopoietic origin. Cell Commun Signal 2023;21:36.

[29] Chen L, Ma L, Yu L. WGA is a probe for migrasomes. Cell Discov 2019;5:13.

[30] Kudlow BA, Kennedy BK, Monnat R Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 2007;8:394–404.

[31] Liu GH, Barkho BZ, Ruiz S, et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 2011;472:221–5.

[32] Gonzalo S, Kreienkamp R, Askjaer P. Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev 2017;33:18–29.

[33] Zhang B, Yan H, Liu X, et al. SenoIndex: S100A8/S100A9 as a novel aging biomarker. Life Med 2023;2:lnad022.

[34] Duan J, Duan J, Zhang Z, et al. Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. Int J Biochem Cell Biol 2005;37:1407–20.

[35] Cheng F, Ji Q, Wang L, et al. Reducing oxidative protein folding alleviates senescence by minimizing ER-to-nucleus H(2) O(2) release. EMBO Rep 2023;24:e56439.

[36] Jiao H, Jiang D, Hu X, et al. Mitocytosis, a migrasome-mediated mito-chondrial quality-control process. Cell 2021;184:2896–2910.e13.

[37] Wang C, Yang K, Liu X, et al. MAVS antagonizes human stem cell senescence as a mitochondrial stabilizer. Research 2023;6:0192.

[38] He Y, Ji Q, Wu Z, et al. 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis. Protein Cell 2023;14:202–16.

[39] Amorim JA, Coppotelli G, Rolo AP, et al. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022;18:243–58.

[40] Shpilka T, Haynes CM. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 2018;19:109–20.

[41] Schleiff E, Turnbull JL. Functional and structural properties of the mitochondrial outer membrane receptor Tom20. Biochemistry 1998;37:13043–51.

[42] Garcia-Montojo M, Doucet-O’Hare T, Henderson L, et al. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol 2018;44:715–38.

[43] Subramanian RP, Wildschutte JH, Russo C, et al. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 2011;8:90.

[44] De Cecco M, Criscione SW, Peckham EJ, et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 2013;12:247–56.

[45] Chen YG, Hur S. Cellular origins of dsRNA, their recognition and consequences. Nat Rev Mol Cell Biol 2022;23:286–301.

[46] Chiappinelli KB, Strissel PL, Desrichard A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 2015;162:974–86.

[47] Lima-Junior DS, Krishnamurthy SR, Bouladoux N, et al. Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota. Cell 2021;184:3794–3811.e19.

[48] Canadas I, Thummalapalli R, Kim JW, et al. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 2018;24:1143–50.

[49] Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev 2020;34:1565–76.

[50] Lopes-Paciencia S, Saint-Germain E, Rowell M-C, et al. The senescence- associated secretory phenotype and its regulation. Cytokine 2019;117:15–22.

[51] Li X, Li C, Zhang W, et al. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther 2023;8:239.

[52] Seth RB, Sun L, Ea C-K, et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 2005;122:669–82.

[53] Schoggins JW, MacDuff DA, Imanaka N, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 2014;505:691–5.

[54] Aging Atlas C. Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 2021;49:D825–30.

[55] Ju Z, Choudhury AR, Rudolph KL. A dual role of p21 in stem cell aging. Ann N Y Acad Sci 2007;1100:333–44.

[56] Robin JD, Magdinier F. Physiological and pathological aging affects chromatin dynamics, structure and function at the nuclear edge. Front Genet 2016;7:153.

[57] Pittenger MF, Discher DE, Péault BM, et al. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med 2019;4:22.

[58] Yan H, Wang R, Ma S, et al. Lineage Landscape: a comprehensive database that records lineage commitment across species. Nucleic Acids Res 2023;51:D1061–6.

[59] Giroud J, Bouriez I, Paulus H, et al. Exploring the communication of the SASP: dynamic, interactive, and adaptive effects on the microenvironment. Int J Mol Sci 2023;24:10788.

[60] Wu D, Xu Y, Ding T, et al. Pairing of integrins with ECM proteins determines migrasome formation. Cell Res 2017;27:1397–400.

[61] Huang Y, Zucker B, Zhang S, et al. Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains. Nat Cell Biol 2019;21:991–1002.

[62] Liang H, Ma X, Zhang Y, et al. The formation of migrasomes is initiated by the assembly of sphingomyelin synthase 2 foci at the leading edge of migrating cells. Nat Cell Biol 2023;25:1173–84.

[63] Ding T, Ji J, Zhang W, et al. The phosphatidylinositol (4,5)-bisphosphate-Rab35 axis regulates migrasome formation. Cell Res 2023;33:617–27.

[64] Zou Z, Long X, Zhao Q, et al. A single-cell transcriptomic atlas of human skin aging. Dev Cell 2021;56:383–397.e8.

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2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.