Changes in Stemness Properties, Differentiation Potential, Oxidative Stress, Senescence and Mitochondrial Function in Wharton’s Jelly Stem Cells of Umbilical Cords of Mothers with Gestational Diabetes Mellitus

Abstract

Gestational diabetes mellitus (GDM) has been associated with an increased risk of maternal and neonatal morbidity. The Wharton’s jelly (WJ) of the umbilical cord (UC) is a useful indicator of the deleterious effects of hyperglycemia on fetal tissues as it represents the fetus embryologically, physiologically and genetically. We studied WJ mesenchymal stem cells (hWJSCs) from UC from mothers without GDM (Normal; n = 3); insulin-controlled GDM mothers (GDMi; n = 3) and diet-controlled GDM mothers (GDMd; n = 3)]. Cell proliferation, stemness markers, telomerase, osteogenic and chondrogenic differentiation, antioxidant enzymes and gene expression for mitochondrial function (ND2, TFAM, PGC1α, and NDUFB9) were significantly lower in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs (P < 0.05). On the other hand, cell cycle inhibitors (p16, p21, p27) and p53 were remarkably up-regulated in GDMi-hWJSCs and GDMd-hWJSCs compared to normal hWJSCs. The results from this study confirmed that maternal hyperglycemia even though managed with insulin or diet, induced changes in the properties of the WJ and its cells. These changes may also be observed in fetal tissues and if true, prevention of the onset of gestational diabetes should be a priority over management. Generation of tissues that simulate those of the fetus such as pancreatic and cardiovascular cells from GDM-hWJSCs by direct differentiation or via induced pluripotent stem cell reprogramming provide possible platforms to evaluate the effects of glucose on specific fetal organ.

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References

  1. 1.

    Michael Weindling, A. (2009). Offspring of diabetic pregnancy: Short-term outcomes. Seminars in Fetal & Neonatal Medicine, 14, 111–118.

    Article  CAS  Google Scholar 

  2. 2.

    Metzger, B. E., Buchanan, T. A., Coustan, D. R., de Leiva, A., Dunger, D. B., Hadden, D. R., Hod, M., Kitzmiller, J. L., Kjos, S. L., Oats, J. N., Pettitt, D. J., Sacks, D. A., & Zoupas, C. (2007). Summary and recommendations of the fifth international workshop-conference on gestational Diabetes mellitus. Diabetes Care, 30(Suppl 2), S251–S260.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    American Diabetes, A. (2012). Diagnosis and classification of diabetes mellitus. Diabetes Care, 35(Suppl 1), S64–S71.

    Article  Google Scholar 

  4. 4.

    Pedersen J. Diabetes mellitus and pregnancy: Present status of the hyperglycaemia--hyperinsulinism theory and the weight of the newborn baby. Postgraduate Medical Journal 1971:Suppl:66–7.

  5. 5.

    Barker, D. J., Winter, P. D., Osmond, C., Margetts, B., & Simmonds, S. J. (1989). Weight in infancy and death from ischaemic heart disease. Lancet, 2, 577–580.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    El-Osta, A., Brasacchio, D., Yao, D., et al. (2008). Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. The Journal of Experimental Medicine, 205, 2409–2417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Marco, L. J., McCloskey, K., Vuillermin, P. J., Burgner, D., Said, J., & Ponsonby, A. L. (2012). Cardiovascular disease risk in the offspring of diabetic women: The impact of the intrauterine environment. Experimental Diabetes Research, 2012, 565160.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Subramanian, A., Fong, C. Y., Biswas, A., & Bongso, A. (2015). Comparative characterization of cells from the various compartments of the human umbilical cord shows that the Wharton's jelly compartment provides the best source of clinically utilizable mesenchymal stem cells. PLoS One, 10, e0127992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Wang, X. Y., Lan, Y., He, W. Y., Zhang, L., Yao, H. Y., Hou, C. M., Tong, Y., Liu, Y. L., Yang, G., Liu, X. D., Yang, X., Liu, B., & Mao, N. (2008). Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos. Blood, 111, 2436–2443.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Singh, S. D. (1986). Gestational diabetes and its effect on the umbilical cord. Early Human Development, 14, 89–98.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Sukarieh, R., Joseph, R., Leow, S. C., Li, Y., Löffler, M., Aris, I. M., Tan, J. H., Teh, A. L., Chen, L., Holbrook, J. D., Ng, K. L., Lee, Y. S., Chong, Y. S., Summers, S. A., Gluckman, P. D., & Stünkel, W. (2014). Molecular pathways reflecting poor intrauterine growth are found in Wharton's jelly-derived mesenchymal stem cells. Human Reproduction, 29, 2287–2301.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Cheung, N. W., Oats, J. J., & McIntyre, H. D. (2005). Australian carbohydrate intolerance study in pregnant women: Implications for the management of gestational diabetes. The Australian & New Zealand Journal of Obstetrics & Gynaecology, 45, 484–485.

    Article  Google Scholar 

  13. 13.

    Brown, J., Grzeskowiak, L., Williamson, K., Downie, M. R., & Crowther, C. A. (2017). Insulin for the treatment of women with gestational diabetes. Cochrane Database of Systematic Reviews, 11, CD012037.

    PubMed  Google Scholar 

  14. 14.

    Fong, C. Y., Richards, M., Manasi, N., Biswas, A., & Bongso, A. (2007). Comparative growth behaviour and characterization of stem cells from human Wharton's jelly. Reproductive Biomedicine Online, 15, 708–718.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Kim, J., Piao, Y., Pak, Y. K., Chung, D., Han, Y. M., Hong, J. S., Jun, E. J., Shim, J. Y., Choi, J., & Kim, C. J. (2015). Umbilical cord mesenchymal stromal cells affected by gestational diabetes mellitus display premature aging and mitochondrial dysfunction. Stem Cells and Development, 24, 575–586.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Wajid, N., Naseem, R., Anwar, S. S., Awan, S. J., Ali, M., Javed, S., & Ali, F. (2015). The effect of gestational diabetes on proliferation capacity and viability of human umbilical cord-derived stromal cells. Cell and Tissue Banking, 16, 389–397.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Amrithraj, A. I., Kodali, A., Nguyen, L., Teo, A. K. K., Chang, C. W., Karnani, N., Ng, K. L., Gluckman, P. D., Chong, Y. S., & Stünkel, W. (2017). Gestational Diabetes alters functions in Offspring's umbilical cord cells with implications for cardiovascular health. Endocrinology, 158, 2102–2112.

    Article  PubMed  Google Scholar 

  18. 18.

    Ezimokhai, M., Rizk, D. E., & Thomas, L. (2001). Abnormal vascular coiling of the umbilical cord in gestational diabetes mellitus. Archives of Physiology and Biochemistry, 109, 209–214.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Alam, M. R., Momen, M. A., Sultana, A. A., & Hassan, S. N. (2015). Gross and Histomorphologic study of the umbilical cord in pre-gestational Diabetes mellitus and gestational Diabetes mellitus. Bangladesh Journal of Anatomy, 12, 25–29.

    Article  Google Scholar 

  20. 20.

    Regev, R. H., Dolfin, T., Eliakim, A., Arnon, S., Bauer, S., Nemet, D., & Litmanovitz, I. (2004). Bone speed of sound in infants of mothers with gestational diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism, 17, 1083–1088.

    Article  PubMed  Google Scholar 

  21. 21.

    Mimouni, F., Steichen, J. J., Tsang, R. C., Hertzberg, V., & Miodovnik, M. (1988). Decreased bone mineral content in infants of diabetic mothers. American Journal of Perinatology, 5, 339–343.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Zhao, Z., & Reece, E. A. (2013). New concepts in diabetic embryopathy. Clinics in Laboratory Medicine, 33, 207–233.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Aguiari, P., Leo, S., Zavan, B., Vindigni, V., Rimessi, A., Bianchi, K., Franzin, C., Cortivo, R., Rossato, M., Vettor, R., Abatangelo, G., Pozzan, T., Pinton, P., & Rizzuto, R. (2008). High glucose induces adipogenic differentiation of muscle-derived stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 1226–1231.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cramer, C., Freisinger, E., Jones, R. K., Slakey, D. P., Dupin, C. L., Newsome, E. R., Alt, E. U., & Izadpanah, R. (2010). Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem Cells and Development, 19, 1875–1884.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Tsai, T. L., Manner, P. A., & Li, W. J. (2013). Regulation of mesenchymal stem cell chondrogenesis by glucose through protein kinase C/transforming growth factor signaling. Osteoarthritis and Cartilage, 21, 368–376.

    Article  PubMed  Google Scholar 

  26. 26.

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 88, 593–602.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Parsch, D., Fellenberg, J., Brummendorf, T. H., Eschlbeck, A. M., & Richter, W. (2004). Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes. J Mol Med (Berl), 82, 49–55.

    Article  CAS  Google Scholar 

  28. 28.

    Stolzing, A., Coleman, N., & Scutt, A. (2006). Glucose-induced replicative senescence in mesenchymal stem cells. Rejuvenation Research, 9, 31–35.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Cernea, S., & Dobreanu, M. (2013). Diabetes and beta cell function: From mechanisms to evaluation and clinical implications. Biochem Med (Zagreb), 23, 266–280.

    Article  CAS  Google Scholar 

  30. 30.

    Robertson, R. P., Harmon, J., Tran, P. O., & Poitout, V. (2004). Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes, 53(Suppl 1), S119–S124.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Kornicka, K., Marycz, K., Marędziak, M., Tomaszewski, K. A., & Nicpoń, J. (2017). The effects of the DNA methyltranfserases inhibitor 5-azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells. Journal of Cellular and Molecular Medicine, 21, 387–401.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Kawamura, M., Heinecke, J. W., & Chait, A. (1994). Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. The Journal of Clinical Investigation, 94, 771–778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Bugger, H., & Abel, E. D. (2010). Mitochondria in the diabetic heart. Cardiovascular Research, 88, 229–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kornicka, K., Houston, J., & Marycz, K. (2018). Dysfunction of mesenchymal stem cells isolated from metabolic syndrome and type 2 diabetic patients as result of oxidative stress and autophagy may limit their potential therapeutic use. Stem Cell Reviews and Reports, 14, 337–345.

    Article  Google Scholar 

  35. 35.

    Marycz, K., Kornicka, K., Basinska, K., & Czyrek, A. (2016). Equine metabolic syndrome affects viability, senescence, and stress factors of equine adipose-derived mesenchymal stromal stem cells: New insight into EqASCs isolated from EMS horses in the context of their aging. Oxidative Medicine and Cellular Longevity, 2016, 1–17.

    Google Scholar 

  36. 36.

    Simmons, R. A. (2006). Developmental origins of diabetes: The role of oxidative stress. Free Radical Biology and Medicine, 40, 917–922.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Troyer, D. L., & Weiss, M. L. (2008). Wharton's jelly-derived cells are a primitive stromal cell population. Stem Cells, 26, 591–599.

    Article  PubMed  Google Scholar 

  38. 38.

    Fong, C. Y., Subramanian, A., Gauthaman, K., Venugopal, J., Biswas, A., Ramakrishna, S., & Bongso, A. (2012). Human umbilical cord Wharton's jelly stem cells undergo enhanced chondrogenic differentiation when grown on nanofibrous scaffolds and in a sequential two-stage culture medium environment. Stem Cell Reviews, 8, 195–209.

    Article  CAS  Google Scholar 

  39. 39.

    Gotherstrom, C. (2007). Immunomodulation by multipotent mesenchymal stromal cells. Transplantation, 84, S35–S37.

    Article  PubMed  Google Scholar 

  40. 40.

    Meirelles Lda, S., Fontes, A. M., Covas, D. T., & Caplan, A. I. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & Growth Factor Reviews, 20, 419–427.

    Article  CAS  Google Scholar 

  41. 41.

    Nemeth, K., Wilson, T., Rada, B., Parmelee, A., Mayer, B., Buzas, E., Falus, A., Key, S., Masszi, T., Karpati, S., & Mezey, E. (2012). Characterization and function of histamine receptors in human bone marrow stromal cells. Stem Cells, 30, 222–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Ms. Cecille Arquillo Laureano, Ms. Cynthia Zapata Tagarino and Ms. Maylene Tan Zipagan for their assistance.

Funding

This work was supported by National University Health System (NUHS) Aspiration Fund (Partner category) [R-174-000-156-720], NUHS Aspiration Fund (New Idea) [R-174-000-155-720] and National Medical Research Council (NMRC) Bedside and Bench Grant [R-174-000-160-511].

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Correspondence to Ariff Bongso or Chui-Yee Fong.

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Kong, C., Subramanian, A., Biswas, A. et al. Changes in Stemness Properties, Differentiation Potential, Oxidative Stress, Senescence and Mitochondrial Function in Wharton’s Jelly Stem Cells of Umbilical Cords of Mothers with Gestational Diabetes Mellitus. Stem Cell Rev and Rep 15, 415–426 (2019). https://doi.org/10.1007/s12015-019-9872-y

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Keywords

  • Gestational diabetes mellitus
  • Wharton’s jelly-derived mesenchymal stem cells
  • Insulin
  • Diet, Stemness
  • Trilineage differentiation
  • Oxidative stress
  • Senescence
  • Mitochondrial function