The Hypoxic Preconditioning Effect On Senescence Cell Process In Cultured Adipose-Derived Mesenchymal Stem Cells (AMSCs)

  • Nadiar Dwi Nuarisa Airlangga University
  • I Gde Rurus Suryawan
  • Andrianto Andrianto


Introduction : Stem cell therapy for myocardial regeneration is expected to increase cardiomyocyte proliferation and trigger neovascularization to improve cardiomyocytes. Mesenchymal Stem Cells (MSCs) are ideal candidates for regenerative medicine and immunotherapy. But low viability of MSCs is a major challenge in this alternative therapy. Therefore, a cytoprotective strategy is needed, one of them is hypoxic preconditioning which can significantly increase survival stem cells after being transplanted. MSCs are known to have a limited life span, after experiencing several splits MSC will enter the senescence process. It is known that hypoxia can also increase cell proliferation and differentiation potential in vitro and in vivo through the role of Octamer-4 (Oct-4) as a regulator of the pluripotency gene.

Methods : Experimental laboratory studies (in vitro studies) using human-AMSCs which were given hypoxic preconditioning, observed as a immunocytochemistry.

Results : The results showed that hypoxic precondition (1% O2) inhibited the senescence process. It can be seen in the lower expression of senescence in hypoxic conditions at P6, P7, P8, P9, P10 compared to normoxic ((p=0,004, p=0,001, p=0,009, p=0,013, p=0,024. There is a significant difference in the senescence expression of each passage in hypoxic and normoxic conditions with the highest expression at P10. In addition, we also observed AMSCs differentiation through the Oct-4 expression. It is showed that Oct-4 expression were higher in hypoxia compared to normoxia on P7, P8, P9, P10 (p=0,009, p=0,009, p=0,030, p=0,0001).

Conclusions : Hypoxic preconditioning have the effect of inhibiting the senescence process on Adipose-derived MSCs (AMSCs) or prolonging their life span. The longer life span of AMSCs is also seen by higher cell differentiation potential from increased expression of Oct-4. However, the mechanism of inhibiting the senescence process in hypoxia in stem cells is still remain unknown.

Keywords: human-Adipose derived Mesenchymal Stem Cell Cultures (h-AMSCs), Hypoxic Preconditioning, Senescence cell, Oct-4.


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Seshadri S, Beiser A, Emberson JR, Whincup PH,
Morris RW. 2010. Lipid Modification : Cardiovascular
Risk Assessment and the Modification of
Blood Lipids for The Primary and Secondary Prevention
of Cardiovascular Disease. NHS National
Institute for Health and Clinical Excellence.
2. Fuster V, Walsh R, Harrington R. Preventive Strategies
For Coronary Artery Disease; Introduction. In:
Hurst’s The Heart. 13th ed. Unites States; 2011.
3. Williams AR, Hare JM. Mesenchymal Stem Cell:
Biology, Pathophysiology, Translation Findings, and
Therapeutic Implications for Cardiac Disease. Circulation.
4. Lim SY, Dilley RJ, Dusting GJ. Cytoprotection and
Preconditioning for Stem Cell Therapy. In: Advances
in Regenerative Medicine. 2011;5:89-118.
5. Sun Q, Zhang Z, Sun Z. 2014. The potential and
challenges of using stem cells for cardiovascular repair
and regeneration. Genes Dis. ; 1(1): 113–9.
6. Elnakish MT, Hassan F, Dakhlallah D, Marsh CB,
Alhaider IA, and Khan M. 2012. MesenchymalStem Cells for Cardiac Regeneration: Translation to
Bedside Reality. Volume 2012, Article ID 646038.
7. Porada CD, Zanjani ED, Almeida-Porada G. Adult
Mesenchymal Stem Cell: A Pluripotent Population
With Multiple Applications. Curr Stem Cell Res &
Therapy Vol 1(3); 2006.
8. Geng YJ. Molecular Mechanisms for Cardiovascular
Stem Cell Apoptosis and Growth in the Hearts with
Atheroscerotic Coronary isease and Ischemic Heart
Failure. Science. Ann NY Acad. 2003;1010:687-97.
9. Hadjipanayai E, Schiling AF. Hypoxia-based Strategies
for Angiogenic Induction-The Dawn of a new
Era for Ischemia Therapy and Tissue Regeneration.
In: Organogenesis. 2013;9:1-12.
10. Sart S, Ma T, Li Y. Preconditioning Stem Cells for
In Vivo Delivery. Bioresearch Open Access. 2014;3:
11. Chen J, Patschan S, Goligorsky MS. Stress-induced
premature senescence of endothelial cells. J
Nephrol. 2008;21(3):337-44.
12. Su T, Dan S, Wang Y. Akt-Oct4 Regulatory Circuit
in Pluripotent Stem Cells. In: Chinese Science Bulletin.
2014;59(10): 936-942.
13. Dulic V. Senescence Regulation by mTOR. Methods
Mol Biol. 2013;965:15-35.
14. Voncken JW, Niessen H, Neufeld B, Rennefahrt
U, Dahlmans V, Kubben N, et al. MAPKAP kinase
3pK phosphorylates and regulates chromatin association
of the pol‐ycomb group protein Bmi1. J Biol
Chem. 2005;280(7):5178-87.
15. Legzdina D, Romanauska A , Nikulshin S, Kozlovska
T, Berzins U. Characterization of Senescence
of Culture-expanded Human Adipose-derived Mesenchymal
Stem Cells. International Journal of Stem
Cells. 2016; 9(1):124-36.
16. Gerland LM, Peyrol S, Lallemand C, Branche R,
et al. Association of increased autophagic inclusions
labeled for b-galactosidase with fibroblastic aging.
Experimental Gerontology. 2003;38:887–95.
17. Zeineddine D, Hammoud AA, Mortada M, Boeuf
H. The Oct4 protein: more than a magic stemness
marker. Am J Stem Cells. 2014;3(2):74-82
18. Dominici et al. Minimal criteria for defining multipotent
mesenchymal stromal cells. The International
Society for Cellular Therapy position statement.
International Society for Cellular Therapy.
Cytotherapy. 2006; 8(4):315- 17.
19. Trivanovi D, Nikoli S, Krsti J, Jaukovi A, Mojsilovi
S,et al. Characteristics of human adipose mesenchymal
stem cells isolated from healthy and cancer
affected people and their interactions with human
breast cancer cell line MCF-7 in vitro. Cell Biol Int.
20. Turinetto V, Vitale E, and Giachino C. Senescence
in Human Mesenchymal Stem Cells: Functional
Changes and Implications in Stem Cell-Based Therapy.
Int. J. Mol. Sci. 2016;17:1164.
21. Choo KB, Tai L, Hymavathee KS, Wong CY, Nhi
Nguyen PN, et al. Oxidative Stress-Induced Premature
Senescence in Wharton’s Jelly Derived
Mesenchymal Stem Cells. Int. J. Med. Sci. 2014;
22. Lee CW, Kang D, Kim AK, Kim DY, Kim DI.
Improvement of Cell Cycle Lifespan and Genetic
Damage Susceptibility of Human Mesenchymal
Stem Cells by Hypoxic Priming. International Journal
of Stem Cells. 2018;11(1):61-67.
23. Hu L, Hu J, Zhao J, Liu J, Ouyang W, et al. Side-by
Side Comparison of the Biological Characteristics
of Human Umbilical Cord and Adipose Tissue-Derived
Mesenchymal Stem Cells. BioMed Research
International. 2013; 1-12.
24. Tsai CC, Su PF, Huang YF, Yew TL, and Hung
SC, “Oct4 and Nanog directly regulate Dnmt1 to
maintain selfrenewal and undifferentiated state in
mesenchymal stem cells,” Molecular Cell. 2012;
25. Piccinato CA, Sertie AL, Torres N, Ferretti M, and
Antonioli E. High OCT4 and Low p16INK4A Expressions
Determine In Vitro Lifespan of Mesenchymal
Stem Cells. Stem Cell International. 2015;
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How to Cite
Nuarisa, N., Suryawan, I. G., & Andrianto, A. (2019). The Hypoxic Preconditioning Effect On Senescence Cell Process In Cultured Adipose-Derived Mesenchymal Stem Cells (AMSCs). Indonesian Journal of Cardiology, 39(3).