International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

Lupus Heart Disease Modeling with Combination of Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Lupus Patient Serum

  • Narae Park (CiSTEM Laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Yeri Alice Rim (CiSTEM Laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Hyerin Jung (CiSTEM Laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Yoojun Nam (YiPSCELL) ;
  • Ji Hyeon Ju (CiSTEM Laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
  • Received : 2021.09.17
  • Accepted : 2021.10.11
  • Published : 2022.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background and Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease mainly affecting young women of childbearing age. SLE affects the skin, joints, muscles, kidneys, lungs, and heart. Cardiovascular complications are common causes of death in patients with SLE. However, the complexity of the cardiovascular system and the rarity of SLE make it difficult to investigate these morbidities. Patient-derived induced pluripotent stem cells (iPSCs) serve as a novel tool for drug screening and pathophysiological studies in the absence of patient samples. Methods and Results: We differentiated CMs from HC- and SLE-iPSCs using 2D culture platforms. SLE-CMs showed decreased proliferation and increased levels of fibrosis and hypertrophy marker expression; however, HC-and SLE-monolayer CMs reacted differently to SLE serum treatment. HC-iPSCs were also differentiated into CMs using 3D spheroid culture and anti-Ro autoantibody was treated along with SLE serum. 3D-HC-CMs generated more mature CMs compared to the CMs generated using 2D culture. The treatment of anti-Ro autoantibody rapidly increased the gene expression of fibrosis, hypertrophy, and apoptosis markers, and altered the calcium signaling in the CMs. Conclusions: iPSC derived cardiomyocytes with patient-derived serum, and anti-Ro antibody treatment could serve in effective autoimmune disease modeling including SLE. We believe that the present study might briefly provide possibilities on the application of a combination of patient-derived materials and iPSCs in disease modeling of autoimmune diseases.

Keywords

Acknowledgement

This work was supported by a grant from the Korea Healthcare Technology R&D Project of the Ministry for Health, Welfare and Family Affairs of the Republic of Korea (No. HI16C2177), and by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) of the Korean Government (Nos. NRF-2019R1A5A2027588, NRF-2020R1A1C3004123, and NRF-2021R1C1C2004688).

References

  1. Nikdoust F, Bolouri E, Tabatabaei SA, Goudarzvand M, Faezi ST. Early diagnosis of cardiac involvement in systemic lupus erythematosus via global longitudinal strain (GLS) by speckle tracking echocardiography. J Cardiovasc Thorac Res 2018;10:231-235 
  2. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel-Aty H, Gutberlet M, Prasad S, Aletras A, Laissy JP, Paterson I, Filipchuk NG, Kumar A, Pauschinger M, Liu P. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475-1487 
  3. Fors Nieves CE, Izmirly PM. Mortality in systemic lupus erythematosus: an updated review. Curr Rheumatol Rep 2016;18:21 
  4. Bjornadal L, Yin L, Granath F, Klareskog L, Ekbom A. Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964-95. J Rheumatol 2004;31:713-719 
  5. Dhakal BP, Kim CH, Al-Kindi SG, Oliveira GH. Heart failure in systemic lupus erythematosus. Trends Cardiovasc Med 2018;28:187-197 
  6. Petrackova A, Smrzova A, Gajdos P, Schubertova M, Schneiderova P, Kromer P, Snasel V, Skacelova M, Mrazek F, Zadrazil J, Horak P, Kriegova E. Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay. Clin Proteomics 2017;14:32 
  7. Yoshimi R, Ueda A, Ozato K, Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system. Clin Dev Immunol 2012;2012:606195 
  8. Joo H, Coquery C, Xue Y, Gayet I, Dillon SR, Punaro M, Zurawski G, Banchereau J, Pascual V, Oh S. Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J Exp Med 2012;209:1335-1348 
  9. Kobayashi R, Mii S, Nakano T, Harada H, Eto H. Neonatal lupus erythematosus in Japan: a review of the literature. Autoimmun Rev 2009;8:462-466 
  10. Prince HE, Hogrefe WR. Evaluation of a line immunoblot assay for detection of antibodies recognizing extractable nuclear antigens. J Clin Lab Anal 1998;12:320-324 
  11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725 
  12. Deng JS, Bair LW Jr, Shen-Schwarz S, Ramsey-Goldman R, Medsger T Jr. Localization of Ro (SS-A) antigen in the cardiac conduction system. Arthritis Rheum 1987;30:1232-1238 
  13. Tseng CE, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin North Am 1997;23:31-54 
  14. Stea EA, Routsias JG, Clancy RM, Buyon JP, Moutsopoulos HM, Tzioufas AG. Anti-La/SSB antiidiotypic antibodies in maternal serum: a marker of low risk for neonatal lupus in an offspring. Arthritis Rheum 2006;54:2228-2234 
  15. Smith MA, Henault J, Karnell JL, Parker ML, Riggs JM, Sinibaldi D, Taylor DK, Ettinger R, Grant EP, Sanjuan MA, Kolbeck R, Petri MA, Casey KA. SLE plasma profiling identifies unique signatures of lupus nephritis and discoid lupus. Sci Rep 2019;9:14433 
  16. Steiman AJ, Gladman DD, Ibanez D, Urowitz MB. Prolonged serologically active clinically quiescent systemic lupus erythematosus: frequency and outcome. J Rheumatol 2010;37:1822-1827 
  17. Rim YA, Nam Y, Park N, Jung H, Jang Y, Lee J, Ju JH. Different chondrogenic potential among human induced pluripotent stem cells from diverse origin primary cells. Stem Cells Int 2018;2018:9432616 
  18. Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 2017;16:115-130 
  19. Li C, Chen S, Zhou Y, Zhao Y, Liu P, Cai J. Application of induced pluripotent stem cell transplants: autologous or allogeneic? Life Sci 2018;212:145-149 
  20. Tang D, Chen Y, He H, Huang J, Chen W, Peng W, Lu Q, Dai Y. Integrated analysis of mRNA, microRNA and protein in systemic lupus erythematosus-specific induced pluripotent stem cells from urine. BMC Genomics 2016;17:488 
  21. Liu C, Oikonomopoulos A, Sayed N, Wu JC. Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 2018;145:dev156166 
  22. Brafman DA. Constructing stem cell microenvironments using bioengineering approaches. Physiol Genomics 2013;45:1123-1135 
  23. Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta 2014;1840:2506-2519 
  24. Hew M, O'Connor K, Edel MJ, Lucas M. The possible future roles for iPSC-derived therapy for autoimmune diseases. J Clin Med 2015;4:1193-1206 
  25. Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 2008;35:2152-2158 
  26. Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA, Lavandero S. Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis 2011;2:e244 
  27. Mohamed AAA, Hammam N, El Zohri MH, Gheita TA. Cardiac manifestations in systemic lupus erythematosus: clinical correlates of subclinical echocardiographic features. Biomed Res Int 2019;2019:2437105 
  28. Chen PY, Chang CH, Hsu CC, Liao YY, Chen KT. Systemic lupus erythematosus presenting with cardiac symptoms. Am J Emerg Med 2014;32:1117-1119 
  29. Guan X, Mack DL, Moreno CM, Strande JL, Mathieu J, Shi Y, Markert CD, Wang Z, Liu G, Lawlor MW, Moorefield EC, Jones TN, Fugate JA, Furth ME, Murry CE, Ruohola-Baker H, Zhang Y, Santana LF, Childers MK. Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery. Stem Cell Res 2014;12:467-480 
  30. Thatava T, Armstrong AS, De Lamo JG, Edukulla R, Khan YK, Sakuma T, Ohmine S, Sundsbak JL, Harris PC, Kudva YC, Ikeda Y. Successful disease-specific induced pluripotent stem cell generation from patients with kidney transplantation. Stem Cell Res Ther 2011;2:48 
  31. Son MY, Lee MO, Jeon H, Seol B, Kim JH, Chang JS, Cho YS. Generation and characterization of integration-free induced pluripotent stem cells from patients with autoimmune disease. Exp Mol Med 2016;48:e232 
  32. Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D'Antoni ML, Debuque R, Chandran A, Wang L, Arora K, Rosenthal NA, Tallquist MD. Revisiting cardiac cellular composition. Circ Res 2016;118:400-409 
  33. Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol 2011;13:497-505 
  34. Behrens AN, Iacovino M, Lohr JL, Ren Y, Zierold C, Harvey RP, Kyba M, Garry DJ, Martin CM. Nkx2-5 mediates differential cardiac differentiation through interaction with Hoxa10. Stem Cells Dev 2013;22:2211-2220 
  35. Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 1999;126:1269-1280 
  36. Franceschini F, Cavazzana I. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity 2005;38:55-63 
  37. Catoggio LJ, Skinner RP, Smith G, Maddison PJ. Systemic lupus erythematosus in the elderly: clinical and serological characteristics. J Rheumatol 1984;11:175-181 
  38. Praprotnik S, Bozic B, Kveder T, Rozman B. Fluctuation of anti-Ro/SS-A antibody levels in patients with systemic lupus erythematosus and Sjogren's syndrome: a prospective study. Clin Exp Rheumatol 1999;17:63-68