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Review

Uncontrolled Oxygen Levels in Cultures of Retinal Pigment Epithelium: Have We Missed the Obvious?

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Pages 651-660 | Received 09 Jan 2022, Accepted 28 Feb 2022, Published online: 25 Apr 2022

References

  • Kolb H. Simple Anatomy of the Retina. In Kolb H, Fernandez E, Nelson R (ed). Webvision: the organization of the retina and visual system. Salt Lake City (UT): University of Utah Health Sciences Center. 1995.
  • Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85(3):845–881. doi:10.1152/physrev.00021.2004.
  • Smith DT. The pigmented epithelium of the embryo chick’'s eye studied in vivo and in vitro. Bull Johns Hopkins Hosp. 1920;31:239–240.
  • Fronk AH, Vargis E. Methods for culturing retinal pigment epithelial cells: a review of current protocols and future recommendations. J Tissue Eng. 2016;7:2041731416650838.
  • Ahmed J, Braun R, Dunn R, Linsenmeier RA. Oxygen distribution in the macaque retina. Invest Ophthalmol Vis Sci. 1993;34(3):516–521.
  • Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003;121(4):547–557. doi:10.1001/archopht.121.4.547.
  • Alder VA, Cringle SJ, Constable IJ. The retinal oxygen profile in cats. Invest Ophthalmol Vis Sci. 1983;24(1):30–36.
  • Lau JC, Linsenmeier RA. Oxygen consumption and distribution in the long-evans rat retina. Exp Eye Res. 2012;102:50–58. doi:10.1016/j.exer.2012.07.004.
  • Linsenmeier RA. Effects of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol. 1986;88(4):521–542. doi:10.1085/jgp.88.4.521.
  • Wion D, Christen T, Barbier EL, Coles JA. PO(2) matters in stem cell culture. Cell Stem Cell. 2009;5(3):242–243. doi:10.1016/j.stem.2009.08.009.
  • Satoru K, Kiyoshi T. Cell handling and culture under controlled oxygen concentration. Biomedical Tissue Culture. 2012;InTech.
  • Place TL, Domann FE, Case AJ. Limitations of oxygen delivery to cells in culture: an underappreciated problem in basic and translational research. Free Radic Biol Med. 2017;113:311–322. doi:10.1016/j.freeradbiomed.2017.10.003.
  • Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age-related macular degeneration. Mol Vis. 1999;5:32.
  • Khaliq A, Jarvis-Evans J, McLeod D, Boulton M. Oxygen modulates the response of the retinal pigment epithelium to basic fibroblast growth factor and epidermal growth factor by receptor regulation. Invest Ophthalmol Vis Sci. 1996;37(2):436–443.
  • Gwiazdowicz DJ, Zawieja B, Olejniczak I, Skubała P, Gdula AK, Coulson SJ. Changing microarthropod communities in front of a receding glacier in the High Arctic. Insects. 2020;11(4):226. doi:10.3390/insects11040226.
  • Hoar RM. Embryology of the eye. Environ Health Perspect. 1982;44:31–34. doi:10.1289/ehp.824431.
  • Davis-Silberman N, Ashery-Padan R. Iris development in vertebrates; genetic and molecular considerations. Brain Res. 2008;1192:17–28. doi:10.1016/j.brainres.2007.03.043.
  • Wang X, Xiong K, Lu L, Gu D, Wang S, Chen J, Xiao H, Zhou G. Developmental origin of the posterior pigmented epithelium of iris. Cell Biochem Biophys. 2015;71(2):1067–1076. doi:10.1007/s12013-014-0310-0.
  • Konari K, Sawada N, Zhong Y, Isomura H, Nakagawa T, Mori M. Development of the blood-retinal barrier in vitro: formation of tight junctions as revealed by occludin and ZO-1 correlates with the barrier function of chick retinal pigment epithelial cells. Exp Eye Res. 1995;61(1):99–108. doi:10.1016/s0014-4835(95)80063-8.
  • Gao H, Hollyfield J. Aging of the human retina: differential loss of neurons and retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1992;33(1):1–17.
  • Warwick R. 1976. Eugene Wolff’s anatomy of the eye and orbit, 7th ed., Philadelphia: WB Saunders Co.
  • Dorey CK, Wu G, Ebenstein D, Garsd A, Weiter J. Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci. 1989;30(8):1691–1699.
  • Mitchell CH. Ion channels of cultured human retinal pigment epithelial cells. London, UK: University of London, Institute of Ophthalmology (United Kingdom), 1994.
  • Simó R, Villarroel M, Corraliza L, Hernández C, Garcia-Ramírez M. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier—implications for the pathogenesis of diabetic retinopathy. J Biomed Biotechnol. 2010;2010:190724. doi:10.1155/2010/190724.
  • Fernandez-Godino R, Garland DL, Pierce EA. Isolation, culture and characterization of primary mouse RPE cells. Nat Protoc. 2016;11(7):1206–1218. doi:10.1038/nprot.2016.065.
  • Pan WW, Wubben TJ, Besirli CG. Photoreceptor metabolic reprogramming: current understanding and therapeutic implications. Commun Biol. 2021;4(1):1–16. doi:10.1038/s42003-021-01765-3.
  • Adler AJ, Southwick RE. Distribution of glucose and lactate in the interphotoreceptor matrix. Ophthalmic Res. 1992;24(4):243–252. doi:10.1159/000267174.
  • Zhang L, Du J, Justus S, Hsu C-W, Bonet-Ponce L, Wu W-H, Tsai Y-T, Wu W-P, Jia Y, Duong JK, et al. Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest. 2016;126(12):4659–4673. doi:10.1172/JCI86905.
  • Venkatesh A, Ma S, Le YZ, Hall MN, Rüegg MA, Punzo C. Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. J Clin Invest. 2015;125(4):1446–1458. doi:10.1172/JCI79766.
  • Kurihara T, Westenskow PD, Gantner ML, Usui Y, Schultz A, Bravo S, Aguilar E, Wittgrove C, Friedlander MS, Paris LP, et al. Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration. Elife. 2016;5:e14319. doi:10.7554/eLife.14319.
  • Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, et al. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest. 2011;121(1):369–383. doi:10.1172/JCI44303.
  • Kanow MA, Giarmarco MM, Jankowski CS, Tsantilas K, Engel AL, Du J, Linton JD, Farnsworth CC, Sloat SR, Rountree A, et al. Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. Elife. 2017;6:e28899. doi:10.7554/eLife.28899.
  • Hurley JB. Retina metabolism and metabolism in the pigmented epithelium: a busy intersection. Annu Rev Vis Sci. 2021;7(1):665–692. doi:10.1146/annurev-vision-100419-115156.
  • Viegas FO, Neuhauss SC. A metabolic landscape for maintaining retina integrity and function. Front Mol Neurosci. 2021;14:60. doi:10.3389/fnmol.2021.656000
  • Kanow M. Dynamic metabolism between the retinal pigmented epithelium and retina reveals a metabolic ecosystem in the eye. Washington: University of Washington, 2019.
  • Li J-H, Xu Z-Y, Li M-J, Zheng W-L, Huang X-M, Xiao F, Cui Y-H, Pan H-W. LC-MS based metabolomics reveals metabolic pathway disturbance in retinal pigment epithelial cells exposed to hydroxychloroquine. Chem Biol Interact. 2020;328:109212. doi:10.1016/j.cbi.2020.109212.
  • Wang J, Westenskow PD, Fang M, Friedlander M, Siuzdak G. Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation. Phil Trans R Soc A. 2016;374(2079):20150376. doi:10.1098/rsta.2015.0376.
  • Keeling E, Chatelet DS, Tan NYT, Khan F, Richards R, Thisainathan T, Goggin P, Page A, Tumbarello DA, Lotery AJ, et al. 3D-reconstructed retinal pigment epithelial cells provide insights into the anatomy of the outer retina. Int J Mol Sci. 2020;21(21):8408. doi:10.3390/ijms21218408.
  • Gouras P, Ivert L, Neuringer M, Nagasaki T. Mitochondrial elongation in the macular RPE of aging monkeys, evidence of metabolic stress. Graefes Arch Clin Exp Ophthalmol. 2016;254(6):1221–1227. doi:10.1007/s00417-016-3342-x.
  • Xiao C, Chen X, Li W, Li L, Wang L, Xie Q, Han H. Automatic mitochondria segmentation for EM data using a 3D supervised convolutional network. Front Neuroanat. 2018;12:92.
  • Tiede L, Cook E, Morsey B, Fox H. Oxygen matters: tissue culture oxygen levels affect mitochondrial function and structure as well as responses to HIV viroproteins. Cell Death Dis. 2011;2(12):e246. doi:10.1038/cddis.2011.128.
  • Miura Y. Retinal pigment epithelium–choroid organ culture. Expert Rev Ophthalmol. 2011;6(6):669–680. doi:10.1586/eop.11.70.
  • Schnichels S, Kiebler T, Hurst J, Maliha AM, Löscher M, Dick HB, Bartz-Schmidt K-U, Joachim SC. Retinal organ cultures as alternative research models. Altern Lab Anim. 2019;47(1):19–29. doi:10.1177/0261192919840092.
  • Eagle H. Amino acid metabolism in mammalian cell cultures. Science. 1959;130(3373):432–437. doi:10.1126/science.130.3373.432.
  • Klettner AK. Retinal pigment epithelium cell culture. Retinal Pigment Epithelium in Health and Disease (p. 295–305), 2020. Switzerland: Springer.
  • Smith EN, D’Antonio-Chronowska A, Greenwald WW, Borja V, Aguiar LR, Pogue R, Matsui H, Benaglio P, Borooah S, D’Antonio M, et al. Human iPSC-derived retinal pigment epithelium: a model system for prioritizing and functionally characterizing causal variants at AMD risk loci. Stem Cell Reports. 2019;12(6):1342–1353. doi:10.1016/j.stemcr.2019.04.012.
  • Matsumoto E, Koide N, Hanzawa H, Kiyama M, Ohta M, Kuwabara J, Takeda S, Takahashi M. Fabricating retinal pigment epithelial cell sheets derived from human induced pluripotent stem cells in an automated closed culture system for regenerative medicine. PLoS One. 2019;14(3):e0212369. doi:10.1371/journal.pone.0212369.
  • Nabi IR, Mathews AP, Cohen-Gould L, Gundersen D, Rodriguez-Boulan E. Immortalization of polarized rat retinal pigment epithelium. J Cell Sci. 1993;104(1):37–49. doi:10.1242/jcs.104.1.37.
  • Mannagh J, Arya DV, Irvine AR. Tissue culture of human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1973;12(1):52–64.
  • Davis AA, Bernstein PS, Bok D, Turner J, Nachtigal M, Hunt RC. A human retinal pigment epithelial cell line that retains epithelial characteristics after prolonged culture. Invest Ophthalmol Vis Sci. 1995;36(5):955–964.
  • Dunn K, Aotaki-Keen A, Putkey F, Hjelmeland LM. ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res. 1996;62(2):155–170. doi:10.1006/exer.1996.0020.
  • Shao Z, Wang H, Zhou X, Guo B, Gao X, Xiao Z, Liu M, Sha J, Jiang C, Luo Y, et al. Spontaneous generation of a novel foetal human retinal pigment epithelium (RPE) cell line available for investigation on phagocytosis and morphogenesis. Cell Prolif. 2017;50(6):e12386. doi:10.1111/cpr.12386.
  • Najafabadi HS, Soheili Z-S, Ganji SM. Behavior of a spontaneously arising human retinal pigment epithelial cell line cultivated on thin alginate film. J Ophthalmic Vis Res. 2015;10(3):286–294. doi:10.4103/2008-322X.170357.
  • Chen M, Muckersie E, Robertson M, Fraczek M, Forrester JV, Xu H. Characterization of a spontaneous mouse retinal pigment epithelial cell line B6-RPE07. Invest Ophthalmol Vis Sci. 2008;49(8):3699–3706. doi:10.1167/iovs.07-1522.
  • Catanuto P, Espinosa-Heidmann D, Pereira-Simon S, Sanchez P, Salas P, Hernandez E, Cousins SW, Elliot SJ. Mouse retinal pigmented epithelial cell lines retain their phenotypic characteristics after transfection with human papilloma virus: a new tool to further the study of RPE biology. Exp Eye Res. 2009;88(1):99–105. doi:10.1016/j.exer.2008.10.013.
  • Newsome D. Retinal pigmented epithelium culture: current applications. Trans Ophthalmol Soc UK. 1983;103:458–466.
  • Koinzer S, Reinecke K, Herdegen T, Roider J, Klettner A. Oxidative stress induces biphasic ERK1/2 activation in the RPE with distinct effects on cell survival at early and late activation. Curr Eye Res. 2015;40(8):853–857. doi:10.3109/02713683.2014.961613.
  • Carreau A, Hafny-Rahbi BE, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med. 2011;15(6):1239–1253. doi:10.1111/j.1582-4934.2011.01258.x.
  • van Buggenum IH, Van der Heijde G, Tangelder G, Reichert-Thoen J. Ocular oxygen measurement. Br J Ophthalmol. 1996;80(6):567–573. doi:10.1136/bjo.80.6.567.
  • Lange CA, Bainbridge JW. Oxygen sensing in retinal health and disease. Ophthalmologica. 2012;227(3):115–131. doi:10.1159/000331418.
  • Hollborn M, Ackmann C, Kuhrt H, Doktor F, Kohen L, Wiedemann P, Bringmann A. Osmotic and hypoxic induction of the complement factor C9 in cultured human retinal pigment epithelial cells: regulation of VEGF and NLRP3 expression. Mol Vis. 2018;24:518–535.
  • Vadlapatla R, Vadlapudi A, Pal D, Mukherji M, Mitra A. Ritonavir inhibits HIF-1α-mediated VEGF expression in retinal pigment epithelial cells in vitro. Eye (Lond)). 2014;28(1):93–101. doi:10.1038/eye.2013.240.
  • Jiang Z, Yang J, Dai A, Wang Y, Li W, Xie Z. Ribosome profiling reveals translational regulation of mammalian cells in response to hypoxic stress. BMC Genom. 2017;18(1):1–12. doi:10.1186/s12864-017-3996-8
  • Fernandes AF, Guo W, Zhang X, Gallagher M, Ivan M, Taylor A, Pereira P, Shang F. Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells. Exp Eye Res. 2006;83(6):1472–1481. doi:10.1016/j.exer.2006.07.024.
  • Notari L, Miller A, Martínez A, Amaral J, Ju M, Robinson G, Smith LEH, Becerra SP. Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia. Invest Ophthalmol Vis Sci. 2005;46(8):2736–2747. doi:10.1167/iovs.04-1489.
  • Nash RW, McKay BS, Burke JM. The response of cultured human retinal pigment epithelium to hypoxia: a comparison to other cell types. Invest Ophthalmol Vis Sci. 1994;35(6):2850–2856.
  • Murugeswari P, Firoz A, Murali S, Vinekar A, Krishna L, Anandula VR, Jeyabalan N, Chevour P, Jayadev C, Shetty R, et al. Vitamin-D3 (α-1, 25(OH) 2D3) protects retinal pigment epithelium from hyperoxic insults. Invest Ophthalmol Vis Sci. 2020;61(2):4–4. doi:10.1167/iovs.61.2.4.
  • Lu L, Hackett SF, Mincey A, Lai H, Campochiaro PA. Effects of different types of oxidative stress in RPE cells. J Cell Physiol. 2006;206(1):119–125. doi:10.1002/jcp.20439.
  • Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. Apmis. 2002;110(6):481–489. doi:10.1034/j.1600-0463.2002.100606.x.
  • Honda S, Hjelmeland LM, Handa JT. The use of hyperoxia to induce chronic mild oxidative stress in RPE cells in vitro. Mol Vis. 2001;7:63–70.
  • Honda S, Hjelmeland LM, Handa JT. Oxidative stress–induced single-strand breaks in chromosomal telomeres of human retinal pigment epithelial cells in vitro. Invest Ophthalmol Vis Sci. 2001;42(9):2139–2144.
  • Honda S, Hjelmeland LM, Handa JT. Senescence associated beta galactosidase activity in human retinal pigment epithelial cells exposed to mild hyperoxia in vitro. Br J Ophthalmol. 2002;86(2):159–162. doi:10.1136/bjo.86.2.159.
  • Sundelin SP, Nilsson SEG. Lipofuscin-formation in retinal pigment epithelial cells is reduced by antioxidants. Free Radic Biol Med. 2001;31(2):217–225. doi:10.1016/S0891-5849(01)00573-1.
  • Yazdani M. Technical aspects of oxygen level regulation in primary cell cultures: a review. Interdiscip Toxicol. 2016;9(3–4):85–89. doi:10.1515/intox-2016-0011.
  • Gille JJP, Joenje H. Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia. Mutat Res. 1992;275(3–6):405–414. doi:10.1016/0921-8734(92)90043-O.
  • Miceli M, Newsome D, Schriver G. Glucose uptake, hexose monophosphate shunt activity, and oxygen consumption in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1990;31(2):277–283.
  • Wigle JC, Castellanos CC. In vitro measurements of oxygen consumption rates in hTERT-RPE cells exposed to low levels of red light. Mechanisms of Photobiomodulation Therapy XI; 2016: International Society for Optics and Photonics. :96950A.
  • Ames A, Li Y-Y, Heher E, Kimble CR. Energy metabolism of rabbit retina as related to function: high cost of Na + transport. J Neurosci. 1992;12(3):840–853. doi:10.1523/JNEUROSCI.12-03-00840.1992.
  • Winkler BS, Christen Y, Doly M, Droy-Lefaix M. A quantitative assessment of glucose metabolism in the isolated rat retina. Les Seminaires Ophthalmologiques d’IPSEN, Vision et Adaptation. 1995;6:78–96.
  • Linsenmeier RA, Zhang HF. Retinal oxygen: from animals to humans. Prog Retin Eye Res. 2017;58:115–151. doi:10.1016/j.preteyeres.2017.01.003.
  • Nöjd N, Lehtonen L, Pietilae S, Vaajasaari H, Ilmarinen T, Skottman H, Suuronen R, Hyttinen J. Microelectrode array in evaluation of RPE functionality. Invest Ophthalmol Vis Sci. 2010;51(13):5252–5252.
  • Levitsky Y, Pegouske DJ, Hammer SS, Frantz NL, Fisher KP, Muchnik AB, Saripalli AR, Kirschner P, Bazil JN, Busik JV, et al. Micro-respirometry of whole cells and isolated mitochondria. RSC Adv. 2019;9(57):33257–33267. doi:10.1039/c9ra05289e.
  • Guarino RD, Dike LE, Haq TA, Rowley JA, Pitner JB, Timmins MR. Method for determining oxygen consumption rates of static cultures from microplate measurements of pericellular dissolved oxygen concentration. Biotechnol Bioeng. 2004;86(7):775–787. doi:10.1002/bit.20072.
  • Al-Ani A, Toms D, Kondro D, Thundathil J, Yu Y, Ungrin M. Oxygenation in cell culture: critical parameters for reproducibility are routinely not reported. PLoS One. 2018;13(10):e0204269. doi:10.1371/journal.pone.0204269.
  • Van der Windt GJ, Chang CH, Pearce EL. Measuring bioenergetics in T cells using a seahorse extracellular flux analyzer. Curr Protoc Immunol. 2016;113(1):3.16 B. 11–13.16 B. 14. doi: 10.1002/0471142735.im0316bs113
  • Hu P, Caro-Maldonado A, Rathmell J, Malek G. Exploring potential differences in the cell energy metabolism of Retinal Pigment Epithelial (RPE) cell culture models. Invest Ophthalmol Vis Sci. 2013;54(15):330–330.
  • Sheu S-J, Liu N-C, Ou C-C, Bee Y-S, Chen S-C, Lin H-C, Chan JY. Resveratrol stimulates mitochondrial bioenergetics to protect retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci. 2013;54(9):6426–6438. doi:10.1167/iovs.13-12024.
  • Hu X, Calton MA, Tang S, Vollrath D. Depletion of mitochondrial DNA in differentiated retinal pigment epithelial cells. Sci Rep. 2019;9(1):1–10. doi:10.1038/s41598-019-51761-1.
  • Karimi P, Gheisari A, Gasparini SJ, Baharvand H, Shekari F, Satarian L, Ader M. Crocetin prevents RPE cells from oxidative stress through protection of cellular metabolic function and activation of ERK1/2. Int J Mol Sci. 2020;21(8):2949. doi:10.3390/ijms21082949.
  • Iacovelli J, Rowe GC, Khadka A, Diaz-Aguilar D, Spencer C, Arany Z, Saint-Geniez M. PGC-1α induces human RPE oxidative metabolism and antioxidant capacity. Invest Ophthalmol Vis Sci. 2016;57(3):1038–1051. doi:10.1167/iovs.15-17758.
  • Khatami M. Na+-linked active transport of ascorbate into cultured bovine retinal pigment epithelial cells: heterologous inhibition by glucose. Membr Biochem. 1987;7(2):115–130. doi:10.3109/09687688709039988.
  • Gstraunthaler G, Seppi T, Pfaller W. Impact of culture conditions, culture media volumes, and glucose content on metabolic properties of renal epithelial cell cultures: are renal cells in tissue culture hypoxic? Cell Physiol Biochem. 1999;9(3):150–172. doi:10.1159/000016312.
  • Vis MA, Ito K, Hofmann S. Impact of culture medium on cellular interactions in in vitro Co-culture systems. Front Bioeng Biotechnol. 2020;8:911. doi:10.3389/fbioe.2020.00911.
  • Oze H, Hirao M, Ebina K, Shi K, Kawato Y, Kaneshiro S, Yoshikawa H, Hashimoto J. Impact of medium volume and oxygen concentration in the incubator on pericellular oxygen concentration and differentiation of murine chondrogenic cell culture. In Vitro Cell Dev Biol Anim. 2012;48(2):123–130. doi:10.1007/s11626-011-9479-3.
  • Wang J, Kolomeyer AM, Zarbin MA, Townes-Anderson E. Organotypic culture of full-thickness adult porcine retina. J Vis Exp. 2011;(49):e2655. doi:10.3791/2655
  • Koizumi A, Zeck G, Ben Y, Masland RH, Jakobs TC. Organotypic culture of physiologically functional adult mammalian retinas. PLoS One. 2007;2(2):e221. doi:10.1371/journal.pone.0000221.
  • Nahmias Y, Kramvis Y, Barbe L, Casali M, Berthiaume F, Yarmush ML. A novel formulation of oxygen-carrying matrix enhances liver-specific function of cultured hepatocytes. Faseb J. 2006;20(14):2531–2533. doi:10.1096/fj.06-6192fje.
  • Stuart JA, Fonseca J, Moradi F, Cunningham C, Seliman B, Worsfold CR, Dolan S, Abando J, Maddalena LA. How supraphysiological oxygen levels in standard cell culture affect oxygen-consuming reactions. Oxid Med Cell Longev. 2018;2018:8238459. doi:10.1155/2018/8238459.
  • Xu R, Ritz BK, Wang Y, Huang J, Zhao C, Gong K, Liu X, Du J. The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected. J Biol Chem. 2020;295(8):2324–2335. doi:10.1074/jbc.RA119.011727.
  • Li B, Zhang T, Liu W, Wang Y, Xu R, Zeng S, Zhang R, Zhu S, Gillies MC, Zhu L, et al. Metabolic features of mouse and human retinas: rods versus cones, macula vs. periphery, retina vs. RPE. iScience 2020;23(11):101672. doi:10.1016/j.isci.2020.101672.
  • Zhang M, Jiang N, Chu Y, Postnikova O, Varghese R, Horvath A, Cheema AK, Golestaneh N. Dysregulated metabolic pathways in age-related macular degeneration. Sci Rep. 2020;10(1):1–14. doi:10.1038/s41598-020-59244-4.
  • Scott LM, Vincent EE, Hudson N, Neal C, Jones N, Lavelle C, Campbell M, Halestrap AP, Dick AD, Theodoropoulou S. Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors. JCI Insight. 2021;6(8):429. doi:10.1172/jci.insight.129429.
  • Du J, Yanagida A, Knight K, Engel AL, Vo AH, Jankowski C, Sadilek M, Tran VTB, Manson MA, Ramakrishnan A, et al. Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. Proc Natl Acad Sci USA. 2016;113(51):14710–14715. doi:10.1073/pnas.1604572113.
  • Brown CN, Emri E, Lengyel I. Investigating the metabolic effects of basal mineral calcification on human RPE cell culture. Invest Ophthalmol Vis Sci. 2021;62(8):2232–2232.
  • Chao JR, Knight K, Engel AL, Jankowski C, Wang Y, Manson MA, Gu H, Djukovic D, Raftery D, Hurley JB, et al. Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. J Biol Chem. 2017;292(31):12895–12905. doi:10.1074/jbc.M117.788422.
  • Bisbach CM, Hass DT, Robbings BM, Rountree AM, Sadilek M, Sweet IR, Hurley JB. Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium. Cell Rep. 2020;31(5):107606. doi:10.1016/j.celrep.2020.107606.
  • Ahluwalia A. Allometric scaling in-vitro. Sci Rep. 2017;7(1):42113–42117. doi:10.1038/srep42113.
  • Sheta EA, Trout H, Gildea JJ, Harding MA, Theodorescu D. Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. Oncogene. 2001;20(52):7624–7634. doi:10.1038/sj.onc.1204972.
  • Samanta D, Semenza GL. Maintenance of redox homeostasis by hypoxia-inducible factors. Redox Biol. 2017;13:331–335. doi:10.1016/j.redox.2017.05.022.
  • Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, Candinas D. HIF‐1 is expressed in normoxic tissue and displays an organ‐specific regulation under systemic hypoxia. Faseb J. 2001;15(13):2445–2453. doi:10.1096/fj.01-0125com.
  • Coassin M, Duncan KG, Bailey KR, Singh A, Schwartz DM. Hypothermia reduces secretion of vascular endothelial growth factor by cultured retinal pigment epithelial cells. Br J Ophthalmol. 2010;94(12):1678–1683. doi:10.1136/bjo.2009.168864.
  • Xiao Q, Zeng S, Ling S, Lv M. Up-regulation of HIF-1alpha and VEGF expression by elevated glucose concentration and hypoxia in cultured human retinal pigment epithelial cells. J Huazhong Univ Sci Technolog Med Sci. 2006;26(4):463–465. doi:10.1007/s11596-006-0422-x.
  • Peniche Silva CJ, Liebsch G, Meier RJ, Gutbrod MS, Balmayor ER, Van Griensven M. A new non-invasive technique for measuring 3D-oxygen gradients in wells during mammalian cell culture. Front Bioeng Biotechnol. 2020;8:595. doi:10.3389/fbioe.2020.00595.

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