EKSPRESI GEN MIRO1 DAN P53 PADA CO-CULTURE WHARTON’S JELLY-MESENCHYMAL STEM CELL DAN JANTUNG TIKUS NEONATUS DIINDUKSI DOXORUBICIN

Zikril Ariliusra

Abstract

Transfer mitokondria interseluler diduga dapat menjadi mekanisme terapi mesenchymal stem cell (MSC) terhadap berbagai penyakit yang diakibatkan oleh gangguan atau kerusakan pada mitokondria, salah satunya kardiomiopati akibat doxorubicin. Tujuan penelitian ini adalah untuk mengetahui peran transfer mitokondria interseluler sebagai mekanisme protektif MSC. Penelitian ex vivo ini menggunakan jantung tikus neonatus yang diberikan doxorubicin dan MSC dengan metode whole organ culture. Pengukuran ekspresi gen Miro1 digunakan sebagai indikator aktivitas transfer mitokondria interseluler dan ekspresi gen p53 sebagai indikator stres sel. Ekspresi gen p53 pada kelompok yang diberikan doxorubicin 20µM selama 30 menit meningkat singnifikan (p<0,05) dibanding kelompok kontrol. Penambahan wharthon’s jelly(WJ)-MSC sebanyak 1x105  atau 1x106 pada menit ke-10 menyebabkan ekspresi gen p53 pada menit ke-30 lebih rendah signifikan (p<0,05) dibanding kelompok perlakuan tanpa penambahan WJ-MSC. Tidak ditemukan korelasi yang signifikan antara ekspresi gen Miro1 dan gen p53 pada kelompok yang mendapatkan WJ-MSC. Pada penelitian ini disimpulkan bahwa transfer mitokondria interseluler tidak berperan signifikan dalam mekanisme terapi WJ-MSC tanpa rekayasa genetik.

Keywords

mitochondrial transfer; whole organ culture; Miro1; tunneling nano tube; TNT

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References

Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med Off J Am Coll Med Genet. 2010 Nov;12(11):655–67.

Brieler JAY, Breeden MA, Tucker J, Louis S. Cardiomyopathy: An Overview. 2017;

Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy : the complexity of a diverse genetic architecture. Nat Publ Group. 2013;1–17.

Semsarian C, Ingles J, Maron MS, Maron BJ. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249–54.

McKenna WJ, Maron BJ, Thiene G. Classification, Epidemiology, and Global Burden of Cardiomyopathies. Circ Res. 2017;121(7):722–30.

Moslehi JJ. Cardiovascular Toxic Effects of Targeted Cancer Therapies. N Engl J Med. 2016 Oct;375(15):1457–67.

Moslehi J, Amgalan D, Kitsis RN. Grounding Cardio-Oncology in Basic and Clinical Science. Circulation. 2017;136(1):3–5.

Mantawy EM, Esmat A, El-bakly WM, Eldin RAS. Mechanistic clues to the protective effect of chrysin against doxorubicin-induced cardiomyopathy : Plausible roles of p53 , MAPK and AKT pathways. 2017;(January):1–13.

Vaseva A V., Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM. P53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell. 2012;149(7):1536–48.

Guo Y, Yu Y, Hu S, Chen Y, Shen Z. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020;

Gao LR, Chen Y, Zhang NK, Yang XL, Liu HL, Wang ZG, et al. Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med. 2015;13(1):162.

Zhang Y, Liang X, Liao S, Wang W, Wang J, Li X, et al. Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy. Sci Rep. 2015 Jun;5:11235.

Gopinath S, Vanamala SK, Gondi CS, Rao JS. Human umbilical cord blood derived stem cells repair doxorubicin-induced pathological cardiac hypertrophy in mice. Biochem Biophys Res Commun. 2010 May;395(3):367–72.

Zhang Y, Yu Z, Jiang D, Liang X, Liao S, Zhang Z, et al. iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy. Stem Cell Rep. 2016;7(4):749–63.

Babenko VA, Silachev DN, Popkov VA, Zorova LD, Pevzner IB, Plotnikov EY, et al. Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery. Mol Basel Switz. 2018 Mar;23(3).

Mahrouf-yorgov M, Augeul L, Crola C, Silva D, Jourdan M, Rigolet M, et al. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. 2017;1224–38.

Modi S, López-doménech G, Halff EF, Covill-cooke C, Ivankovic D, Melandri D, et al. sites and link cristae organization to the mitochondrial transport machinery. Nat Commun. 2019;17–9.

Kontou G, Antonoudiou P, Podpolny M, Szulc BR, Arancibia-carcamo IL, Higgs NF, et al. Miro1-dependent mitochondrial dynamics in parvalbumin interneurons. 2021;1–28.

Alshaabi H, Shannon N, Gravelle R, Milczarek S, Messier T, Cunniff B. Redox Biology Miro1-mediated mitochondrial positioning supports subcellular redox status. Redox Biol. 2021;38(November 2020):101818.

Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S, Rehman R, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014;33(9):994–1010.

Yarni SD, Ali H, Tjong DH. The Effect of Mesenchymal Stem Cell Wharton Jelly on Alzheimer ’ s Rat with Y-Maze Test Method. 2021;44(2):112–6.

Wang Y, Cui J, Sun X, Zhang Y. Tunneling-nanotube development in astrocytes depends on p53 activation. Cell Death Differ. 2011;18(4):732–42.

Lin RW, Ho CJ, Chen HW, Pao YH, Chen LE, Yang MC, et al. P53 enhances apoptosis induced by doxorubicin only under conditions of severe DNA damage. Cell Cycle Georget Tex. 2018;17(17):2175–86.

Chen Y, Liu K, Shi Y, Shao C. The tango of ROS and p53 in tissue stem cells. Vol. 25, Cell death and differentiation. 2018. p. 639–41.

Liu B, Chen Y, St Clair DK. ROS and p53: a versatile partnership. Free Radic Biol Med. 2008 Apr;44(8):1529–35.

Dhar SK, Xu Y, Chen Y, St Clair DK. Specificity protein 1-dependent p53-mediated suppression of human manganese superoxide dismutase gene expression. J Biol Chem. 2006 Aug;281(31):21698–709.

Cardaci S, Filomeni G, Rotilio G, Ciriolo MR. Reactive oxygen species mediate p53 activation and apoptosis induced by sodium nitroprusside in SH-SY5Y cells. Mol Pharmacol. 2008 Nov;74(5):1234–45.

Sun X, Wang Y, Zhang J, Tu J, Wang XJ, Su XD, et al. Tunneling-nanotube direction determination in neurons and astrocytes. Cell Death Dis. 2012 Dec;3(12):e438.

Watkins SC, Salter RD. Functional Connectivity between Immune Cells Mediated by Tunneling Nanotubules. Immunity. 2005 Sep 1;23(3):309–18.

Shen J, Wu JM, Hu GM, Li MZ, Cong WW, Feng YN, et al. Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the β-adrenergic receptor. Cell Death Dis. 2020;11(11):958.

Konari N, Nagaishi K, Kikuchi S, Fujimiya M. Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo. Sci Rep. 2019;9(1):1–14.

Sweeney HL, Holzbaur ELF. Motor Proteins. Cold Spring Harb Perspect Biol. 2018 May;10(5).

King SJ, Schroer TA. Dynactin increases the processivity of the cytoplasmic dynein motor. Nat Cell Biol. 2000;2(1):20–4.

Toba S, Watanabe TM, Yamaguchi-Okimoto L, Toyoshima YY, Higuchi H. Overlapping hand-over-hand mechanism of single molecular motility of cytoplasmic dynein. Proc Natl Acad Sci. 2006;103(15):5741–5.

Ando J, Shima T, Kanazawa R, Shimo-Kon R, Nakamura A, Yamamoto M, et al. Small stepping motion of processive dynein revealed by load-free high-speed single-particle tracking. Sci Rep. 2020;10(1):1080.

Nitzsche F, Müller C, Lukomska B, Jolkkonen J, Deten A, Boltze J. Concise Review: MSC Adhesion Cascade-Insights into Homing and Transendothelial Migration. Stem Cells Dayt Ohio. 2017 Jun;35(6):1446–60.

Liesveld JL, Sharma N, Aljitawi OS. Stem cell homing: From physiology to therapeutics. Stem Cells. 2020 Oct 1;38(10):1241–53.

Kontou G, Antonoudiou P, Podpolny M, Szulc BR, Arancibia-Carcamo IL, Higgs NF, et al. Miro1-dependent mitochondrial dynamics in parvalbumin interneurons. eLife. 2021 Jun;10.



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