AORTIC ENDOTHELIAL CELL PROLIFERATION INDUCED BY EXOSOMES OBTAINED FROM iPSC UNDER THE ACTION OF VARIOUS MODULATORS

  • E. BITERE “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Cătălina Anda (AVRAM) ZAHARIA “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Carmen (AMITITELOAIE) GENTIMIR “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • I. CAZAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • M. COSTULEANU “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Abstract

Back­ground: Extracellular vesicles (also known as EVs), secreted naturally by all cells, are known to act as mediators for intercellular communication. Aim: The goal of our study was represented by the quantification of rat aortic endothelial cell proliferation in culture in the presence of pluripotent stem cells (iPSC), chemically-induced from rat aortic smooth muscle cells (in co-culture) or in the presence of exosomes obtained, as a supernatant, from the culture medium of the latter cells, in the presence of 0.5 µM trichostatin A, 1 µM 6-mercaptopurine, 2 µM triamterene and 2 µM metformin. Material and methods: We used flow cytometry to quantify cell proliferation, using a membrane-permeable, tetramethylrodamine-based cellular tracking agent, 48 hours after inclusion in the culture medium.  Results: The best proliferation for aortic endothelial cells, in the presence of exosomes obtained from the culture supernatant of pluripotent stem cells, chemically-induced from vascular smooth muscle cells, was obtained when grew these latest cell types on 3D biosupports and treated with 2 µM  metformin. Conclusions: It is suggested that epigenetic changes, genome stabilization, and, especially, reprogramming of energy metabolism, result in the release of exosomes from induced pluripotent stem cells that have the ability to significantly amplify aortic endothelial cell proliferation in culture.

Author Biographies

E. BITERE, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Dental Medicine
Department of Physiopathology
Ph.D. Student

Cătălina Anda (AVRAM) ZAHARIA, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Dental Medicine
Department of Physiopathology
Ph.D. Student

Carmen (AMITITELOAIE) GENTIMIR, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Dental Medicine
Department of Physiopathology
Ph.D. Student

I. CAZAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Dental Medicine
Department of Physiopathology
Ph.D. Student

M. COSTULEANU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Dental Medicine
Department of Physiopathology

References

1. Cravedi P, Farouk S, Angeletti A, et al. Regenerative immunology: the immunological reaction to biomaterials. Transpl Int 2017; 30(12): 1199-1208.
2. Yu J, Hu K, Smuga-Otto K, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009; 324(5928): 797-801.
3. Klein D. iPSCs-based generation of vascular cells: reprogramming approaches and applications. Cell Mol Life Sci 2018; 75(8): 1411-1433.
4. Vallabhaneni KC, Haller H, Dumler I. Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes. Stem Cells Dev 2012; 21(17): 3104-3113.
5. Long Y, Wang M, Gu H and Xie X. Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Res 2015; 25(10): 1171-1174.
6. Wang W, Yang J, Liu H, et al. Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci U S A. 2011; 108(45): 18283-18288.
7. Wang D, Sang H, Zhang K, et al. Stat3 phosphorylation is required for embryonic stem cells ground state maintenance in 2i culture media. Oncotarget 2017; 8(19): 31227-31237.
8. Lobb RJ, Becker M, Wen SW, et al. Optimized exozome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles 2015; 4: 27031.
9. Park JJ, Kwon YW, Kim JW, et al. Coadministration of endothelial and smooth muscle cells derived from human induced pluripotent stem cells as a therapy for critical limb ischemia. Stem Cells Transl Med 2021; 10(3): 414-426.
10. Cioloca DP, Foia L, Holban C, et al. Systemic Diabetic Context-Induced Biochemical Periodontal Alterations in Children. Rev Chim (Bucharest). 2016; 67(12): 2409-2412.
11. Kim H, Lee JW, Han G, Kim K, Yang Y, Kim SH. Extracellular Vesicles as Potential Theranostic Platforms for Skin Diseases and Aging. Pharmaceutics. 2021; 13(5): 760.
12. Shao S, Fang H, Li Q, Wang G. Extracellular vesicles in Inflammatory Skin Disorders: from Pathophysiology to Treatment. Theranostics 2020; 10(22): 9937-9955.
13. Acatrinei D, Gentimir C, Zaharia C, et al. Relationships of NR4A1 Agonists Biochemical Effects with Pre-B Lymphocytes Apoptosis. Rev Chim (Bucharest) 2016; 67(1): 57-60.
14. Lelek J, Zuba-Surma EK. Perspectives for Future Use of Extracellular Vesicles from Umbilical Cord- and Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells in Regenerative Therapies-Synthetic Review. Int J Mol Sci 2020; 21(3): 799.
15. Petrescu G, Costuleanu M, Slatineanu SM, Costuleanu N, Foia L, Costuleanu A. Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity. J Renin-Angio-Aldo S 2001; 2(3): 180-187.
16. Manchon E, Hirt N, Bouaziz JD, Jabrane-Ferrat N, Al-Daccak R. Stem Cells-Derived Extracellular Vesicles: Potential Therapeutics for Wound Healing in Chronic Inflammatory Skin Diseases. Int J Mol Sci 2021; 22(6): 3130.
17. Tsiapalis D, O'Driscoll L. Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engi-neering and Regenerative Medicine Applications. Cells 2020; 9(4): 991.
Published
2021-12-30