Stanniocalcin 2 enhances mesenchymal stem cell survival by suppressing oxidative stress

  • Kim, Pyung-Hwan ;
  • Na, Sang-Su ;
  • Lee, Bomnaerin ;
  • Kim, Joo-Hyun ;
  • Cho, Je-Yoel
  • Received : 2015.07.23
  • Accepted : 2015.09.25
  • Published : 2015.12.31


To overcome the disadvantages of stem cell-based cell therapy like low cell survival at the disease site, we used stanniocalcin 2 (STC2), a family of secreted glycoprotein hormones that function to inhibit apoptosis and oxidative damage and to induce proliferation. STC2 gene was transfected into two kinds of stem cells to prolong cell survival and protect the cells from the damage by oxidative stress. The stem cells expressing STC2 exhibited increased cell viability and improved cell survival as well as elevated expression of the pluripotency and self-renewal markers (Oct4 and Nanog) under sub-lethal oxidative conditions. Up-regulation of CDK2 and CDK4 and down-regulation of cell cycle inhibitors p16 and p21 were observed after the delivery of STC2. Furthermore, STC2 transduction activated pAKT and pERK 1/2 signal pathways. Taken together, the STC2 can be used to enhance cell survival and maintain long-term stemness in therapeutic use of stem cells.


Mesenchymal stem cells;Oxidative stress;Stanniocalcin-2;Stem cell-based therapy


  1. Hsiao ST, Dilley RJ, Dusting GJ and Lim SY (2014) Ischemic preconditioning for cell-based therapy and tissue engineering. Pharmacol Ther 142, 141-153
  2. Satyanarayana A and Kaldis P (2009) Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 28, 2925-2939
  3. Hydbring P and Larsson LG (2010) Cdk2: a key regulator of the senescence control function of Myc. Aging (Albany NY) 2, 244-250
  4. Gogolin S, Ehemann V, Becker G et al (2013) CDK4 inhibition restores G(1)-S arrest in MYCN-amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage. Cell Cycle 12, 1091-1104
  5. Romanov VS, Pospelov VA and Pospelova TV (2012) Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis. Biochemistry (Mosc) 77, 575-584
  6. Sheppard KE and McArthur GA (2013) The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res 19, 5320-5328
  7. Tsai CC, Su PF, Huang YF, Yew TL and Hung SC (2012) Oct4 and Nanog directly regulate Dnmt1 to maintain self-renewal and undifferentiated state in mesenchymal stem cells. Mol Cell 47, 169-182
  8. Baer PC, Griesche N, Luttmann W, Schubert R, Luttmann A and Geiger H (2010) Human adipose-derived mesenchymal stem cells in vitro: evaluation of an optimal expansion medium preserving stemness. Cytotherapy 12, 96-106
  9. Go MJ, Takenaka C and Ohgushi H (2008) Forced expression of Sox2 or Nanog in human bone marrow derived mesenchymal stem cells maintains their expansion and differentiation capabilities. Exp Cell Res 314, 1147-1154
  10. Das B, Bayat-Mokhtari R, Tsui M et al (2012) HIF-2alpha suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells. Stem Cells 30, 1685-1695
  11. Liu TC, Ismail S, Brennan O, Hastings C and Duffy GP (2013) Encapsulation of cardiac stem cells in superoxide dismutase-loaded alginate prevents doxorubicin-mediated toxicity. J Tissue Eng Regen Med 7, 302-311
  12. Zhong J, Chan A, Morad L, Kornblum HI, Fan G and Carmichael ST (2010) Hydrogel matrix to support stem cell survival after brain transplantation in stroke. Neurorehabil Neural Repair 24, 636-644
  13. Kim PH, Yim HG, Choi YJ et al (2014) Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization. J Control Release 187, 1-13
  14. Okabe H, Satoh S, Kato T et al (2001) Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61, 2129-2137
  15. Bouras T, Southey MC, Chang AC et al (2002) Stanniocalcin 2 is an estrogen-responsive gene coexpressed with the estrogen receptor in human breast cancer. Cancer Res 62, 1289-1295
  16. Wang H, Wu K, Sun Y et al (2012) STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro. BMB Rep 45, 629-634
  17. de Almeida PE, Ransohoff JD, Nahid A and Wu JC (2013) Immunogenicity of pluripotent stem cells and their derivatives. Circ Res 112, 549-561
  18. Le Blanc K (2006) Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy 8, 559-561
  19. Chang AC, Jellinek DA and Reddel RR (2003) Mammalian stanniocalcins and cancer. Endocr Relat Cancer 10, 359-373
  20. Tamura S, Oshima T, Yoshihara K et al (2011) Clinical significance of STC1 gene expression in patients with colorectal cancer. Anticancer Res 31, 325-329
  21. Fujiwara Y, Sugita Y, Nakamori S et al (2000) Assessment of Stanniocalcin-1 mRNA as a molecular marker for micrometastases of various human cancers. Int J Oncol 16, 799-804
  22. Kim SJ, Ko JH, Yun JH et al (2013) Stanniocalcin-1 protects retinal ganglion cells by inhibiting apoptosis and oxidative damage. PLoS One 8, e63749
  23. Wu LM, Hui L, Guo R et al (2014) Stanniocalcin-1 protects bovine intestinal epithelial cells from oxidative stress-induced damage. J Vet Sci 15, 475-483
  24. Wu S, Yoshiko Y and De Luca F (2006) Stanniocalcin 1 acts as a paracrine regulator of growth plate chondrogenesis. J Biol Chem 281, 5120-5127
  25. Westberg JA, Serlachius M, Lankila P, Penkowa M, Hidalgo J and Andersson LC (2007) Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling. Stroke 38, 1025-1030
  26. Levy O, Zhao W, Mortensen LJ et al (2013) mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation. Blood 122, e23-32
  27. Baghbaderani BA, Mukhida K, Hong M, Mendez I and Behie LA (2011) A review of bioreactor protocols for human neural precursor cell expansion in preparation for clinical trials. Curr Stem Cell Res Ther 6, 229-254
  28. Wang K, Zhang T, Dong Q, Nice EC, Huang C and Wei Y (2013) Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis 4, e537
  29. Mimeault M, Hauke R and Batra SK (2007) Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther 82, 252-264
  30. Estrada JC, Torres Y, Benguria A et al (2013) Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy. Cell Death Dis 4, e691
  31. Sart S, Ma T and Li Y (2014) Preconditioning stem cells for in vivo delivery. Biores Open Access 3, 137-149
  32. Salem HK and Thiemermann C (2010) Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28, 585-596
  33. Sotiropoulou PA, Perez SA, Salagianni M, Baxevanis CN and Papamichail M (2006) Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells. Stem Cells 24, 462-471
  34. Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A and Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7, 14
  35. Bahmani B, Roudkenar MH, Halabian R, Jahanian-Najafabadi A, Amiri F and Jalili MA (2014) Lipocalin 2 decreases senescence of bone marrow-derived mesenchymal stem cells under sub-lethal doses of oxidative stress. Cell Stress Chaperones 19, 685-693
  36. Sakata H, Niizuma K, Wakai T, Narasimhan P, Maier CM and Chan PH (2012) Neural stem cells genetically modified to overexpress cu/zn-superoxide dismutase enhance amelioration of ischemic stroke in mice. Stroke 43, 2423-2429
  37. Yeung BH, Law AY and Wong CK (2012) Evolution and roles of stanniocalcin. Mol Cell Endocrinol 349, 272-280
  38. Wagner GF and Dimattia GE (2006) The stanniocalcin family of proteins. J Exp Zool A Comp Exp Biol 305, 769-780

Cited by

  1. STC2 as a novel mediator for Mus81-dependent proliferation and survival in hepatocellular carcinoma vol.388, 2017,
  2. Antioxidant effects of selenocysteine on replicative senescence in human adipose-derived mesenchymal stem cells vol.50, pp.11, 2017,
  3. Stanniocalcin 2 Regulates Non-capacitative Ca2+ Entry and Aggregation in Mouse Platelets vol.9, pp.1664-042X, 2018,
  4. RNA sequencing-based analysis of the laying hen uterus revealed the novel genes and biological pathways involved in the eggshell biomineralization vol.8, pp.1, 2018,
  5. A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of the Proteins Secreted by Human Adipose-Derived Mesenchymal Stem Cells vol.27, pp.10, 2018,
  6. Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic NETs vol.25, pp.6, 2018,
  7. Superoxide dismutase 3 protects mesenchymal stem cells through enhanced autophagy and regulation of FoxO3a trafficking vol.51, pp.7, 2018,
  8. Stanniocalcin-2 contributes to mesenchymal stromal cells attenuating murine contact hypersensitivity mainly via reducing CD8+ Tc1 cells vol.9, pp.5, 2018,
  9. Stanniocalcin-2 May Be a Potentially Valuable Prognostic Marker in Endometrial Cancer: a Preliminary Study pp.1532-2807, 2019,


Grant : 세포추적용 무영향 표지분자와 성장인자 발현 줄기세포를 활용한 맞춤형 세포치료 기술 개발