exopher

{{COI|date=January 2023}}{{Primary sources|date=January 2023}}

File:PVM Exopher Labeled-1.jpg

Exophers are a type of membrane-bound extracellular vesicle (EV) that are released by budding out of cells into the extracellular space. Exophers can be released by neurons{{Cite journal | doi = 10.1038/nature21362 | last1 = Melentijevic | first1 = I | last2 = Toth | first2 = ML | last3 = Arnold | first3 = ML | last4 = Guasp | first4 = RJ | last5 = Harinath | first5 = G | last6 = Nguyen | first6 = KC | last7 = Taub | first7 = D| last8 = Parker | first8 = JA | last9 = Neri | first9 = C| last10 = Gabel | first10 = CV | last11 = Hall | first11 = DH| last12 = Driscoll | first12 = M | title = C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress | year = 2017 | journal = Nature | volume = 542(7641) | issue = 7641 | pages = 367–371 | pmid = 28178240 | pmc = 5336134 | bibcode = 2017Natur.542..367M }} and muscle{{Cite journal | doi = 10.15252/embr.202052071| last1 = Turek | first1 = M | last2 = Banasiak | first2 = K | last3 = Piechota | first3 = M | last4 = Shanmugam | first4 = N | last5 = Macias | first5 = M | last6 = Śliwińska | first6 = MA | last7 = Niklewicz | first7 = M| last8 = Kowalski | first8 = K | last9 = Nowak | first9 = N| last10 = Chacinska | first10 = A | last11 = Pokrzywa | first11 = P | title = Muscle-derived exophers promote reproductive fitness | year = 2021 | journal = EMBO Rep. | volume = 22 | issue = 8 | pages = e52071 | pmid = 34288362 | pmc = 8339713 }} in the nematode Caenorhabditis elegans and also from murine cardiomyocytes.{{cite journal | vauthors = Nicolás-Ávila JA, Lechuga-Vieco AV, Esteban-Martínez L, Sánchez-Díaz M, Díaz-García E, Santiago DJ, Rubio-Ponce A, Li JL, Balachander A, Quintana JA, Martínez-de-Mena R, Castejón-Vega B, Pun-García A, Través PG, Bonzón-Kulichenko E, García-Marqués F, Cussó L, A-González N, González-Guerra A, Roche-Molina M, Martin-Salamanca S, Crainiciuc G, Guzmán G, Larrazabal J, Herrero-Galán E, Alegre-Cebollada J, Lemke G, Rothlin CV, Jimenez-Borreguero LJ, Reyes G, Castrillo A, Desco M, Muñoz-Cánoves P, Ibáñez B, Torres M, Ng LG, Priori SG, Bueno H, Vázquez J, Cordero MD, Bernal JA, Enríquez JA, Hidalgo A | display-authors = 6| title = A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart | journal = Cell | volume = 183 | pages = 94–109 | date = 2020 | issue = 1| pmid = 32937105 | doi = 10.1016/j.cell.2020.08.031 | s2cid = 221716195| doi-access = free | hdl = 10261/226682 | hdl-access = free }} Exophers were first discovered in 2017 in the lab of Monica Driscoll at Rutgers University.{{Cite journal |last=Neff |first=Ellen P. |date=2017-04-19 |title=C. elegans takes out the trash |url=https://www.nature.com/articles/laban.1264 |journal=Lab Animal |language=en |volume=46 |issue=5 |pages=189–189 |doi=10.1038/laban.1264 |issn=1548-4475}}

Exophers are notable for their large size, averaging approximately four microns in diameter, and they are able to expel whole organelles, such as mitochondria and lysosomes as cargo. An exopher can initially remain attached to the cell that produced it by a membranous filament that resembles a tunneling nanotube. Exophers share similarities with large oncosomes, but they differ in that they are produced by physiologically normal cells instead of aberrant cells associated with tumors.{{cite journal | vauthors = Meehan B, Rak J, Di Vizio D | title = Oncosomes - large and small: what are they, where they came from? | journal = Journal of Extracellular Vesicles | volume = 5 | issue = | pages = 33109 | date = 2016 | pmid = 27680302 | doi = 10.3402/jev.v5.33109 | pmc = 5040817 }}

Exopher production is thought to be a mechanism cells use to preserve homeostasis. Exophers are produced in response to numerous stressors including intracellular protein aggregation, reactive oxygen species (ROS), heat, osmotic hyertonicity, starvation,{{cite journal | last1 = Cooper | first1 = JF | last2 = Guasp | first2 = RJ | last3 = Arnold | first3 = ML | last4 = Grant | first4 = BD | last5 = Driscoll | first5 = M | title = Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling | journal = Proc Natl Acad Sci USA | volume = 118 | pages = e2101410118 | date = 2021 | issue = 36 | pmid = 34475208 | doi = 10.1073/pnas.2101410118| pmc=8433523 | doi-access = free }} and even space flight.{{cite journal | vauthors = Laranjeiro R, Harinath G, Pollard AK, Gaffney CJ, Deane CS, Vanapalli SA, Etheridge T, Szewczyk NJ, Driscoll M | title = Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult Caenorhabditis elegans | journal = iScience | volume = 24 | pages = 102105 | date = 2021 | issue = 2 | pmid = 33659873 | doi = 10.1016/j.isci.2021.102105 | pmc = 7890410 | bibcode = 2021iSci...24j2105L | hdl = 10871/126285 | hdl-access = free }} Extracellular signaling receptor MERTK, expressed by cardiac-resident macrophages, is necessary for exopher clearance by phagocytosis in mouse-derived cardiac tissue.

Exophers may be relevant to disease. In mouse heart, eliminating macrophages or blocking their ability to engulf exophers lead to inflammation and ventricular dysregulation. Exophers may also promote pathological protein spreading in neurodegenerative diseases due to their ability to carry aggregated proteins outside of neurons, including human huntingtin protein.