Stem Cell Reviews and Reports

, Volume 12, Issue 3, pp 285–297 | Cite as

Mesenchymal Stem/Stromal Cells Derived From a Reproductive Tissue Niche Under Oxidative Stress Have High Aldehyde Dehydrogenase Activity

  • Gina D. Kusuma
  • Mohamed H. Abumaree
  • Mark D. Pertile
  • Anthony V. Perkins
  • Shaun P. Brennecke
  • Bill KalionisEmail author


The use of mesenchymal stem/stromal cells (MSC) in regenerative medicine often requires MSC to function in environments of high oxidative stress. Human pregnancy is a condition where the mother’s tissues, and in particular her circulatory system, are exposed to increased levels of oxidative stress. MSC in the maternal decidua basalis (DMSC) are in a vascular niche, and thus would be exposed to oxidative stress products in the maternal circulation. Aldehyde dehydrogenases (ALDH) are a large family of enzymes which detoxify aldehydes and thereby protect stem cells against oxidative damage. A subpopulation of MSC express high levels of ALDH (ALDHbr) and these are more potent in repairing and regenerating tissues. DMSC was compared with chorionic villous MSC (CMSC) derived from the human placenta. CMSC reside in vascular niche and are exposed to the fetal circulation, which is in lower oxidative state. We screened an ALDH isozyme cDNA array and determined that relative to CMSC, DMSC expressed high levels of ALDH1 family members, predominantly ALDH1A1. Immunocytochemistry gave qualitative confirmation at the protein level. Immunofluorescence detected ALDH1 immunoreactivity in the DMSC and CMSC vascular niche. The percentage of ALDHbr cells was calculated by Aldefluor assay and DMSC showed a significantly higher percentage of ALDHbr cells than CMSC. Finally, flow sorted ALDHbr cells were functionally potent in colony forming unit assays. DMSC, which are derived from pregnancy tissues that are naturally exposed to high levels of oxidative stress, may be better candidates for regenerative therapies where MSC must function in high oxidative stress environments.


Mesenchymal stem cells Chorionic villi Decidua Placenta Aldehyde dehydrogenase 



The authors wish to thank the clinical research midwives, Sue Duggan and Moira Stewart, for patient sample collection at the Royal Women’s Hospital. We also thank Dr. Matthew Burton for his advice with flow cytometry gating, Melissa Duggan and Debora Singgih for their technical assistance. Financial support was provided by research funding from King Abdullah International Medical Research Centre (Grant No. RC08/114), the Royal Women’s Hospital Foundation, and an Australian Stem Cell Centre Postgraduate Scholarship.


  1. 1.
    Baksh, D., Song, L., & Tuan, R. S. (2004). Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. Journal of Cellular and Molecular Medicine, 8(3), 301–316.CrossRefPubMedGoogle Scholar
  2. 2.
    da Silva Meirelles, L., Caplan, A. I., & Nardi, N. B. (2008). In search of the in vivo identity of mesenchymal stem cells. Stem Cells, 26(9), 2287–2299.CrossRefPubMedGoogle Scholar
  3. 3.
    English, K., French, A., & Wood, K. J. (2010). Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell, 7(4), 431–442.CrossRefPubMedGoogle Scholar
  4. 4.
    Valle-Prieto, A., & Conget, P. A. (2010). Human Mesenchymal Stem Cells Efficiently Manage Oxidative Stress. Stem Cells and Development, 19(12), 1885–1893.CrossRefPubMedGoogle Scholar
  5. 5.
    Lodi, D., Iannitti, T., & Palmieri, B. (2011). Stem cells in clinical practice: applications and warnings. Journal of Experimental & Clinical Cancer Research, 30(1), 9.CrossRefGoogle Scholar
  6. 6.
    Mimeault, M., & Batra, S. K. (2006). Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. Stem Cells, 24(11), 2319–2345.CrossRefPubMedGoogle Scholar
  7. 7.
    Peterson, K. M., et al. (2011). Improved survival of mesenchymal stromal cell after hypoxia preconditioning: Role of oxidative stress. Life Sciences, 88(1–2), 65–73.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Raijmakers, M. T. M., et al. (2008). The transient increase of oxidative stress during normal pregnancy is higher and persists after delivery in women with pre-eclampsia. European Journal of Obstetrics & Gynecology and Reproductive Biology, 138(1), 39–44.CrossRefGoogle Scholar
  9. 9.
    Ashok, A., A. Nabil, & Botros, R. (2013). Studies on Women's Health. Oxidative Stress in Applied Basic Research and Clinical Practice ed. N.A. Ashok Agarwal, Botros Rizk, New York: Humana Press.Google Scholar
  10. 10.
    Castrechini, N. M., et al. (2010). Mesenchymal stem cells in human placental chorionic villi reside in a vascular Niche. Placenta, 31(3), 203–212.CrossRefPubMedGoogle Scholar
  11. 11.
    Kusuma, G.D., et al., (2015). Mesenchymal stem cells reside in a vascular niche in the decidua basalis and are absent in remodelled spiral arterioles. Placenta.Google Scholar
  12. 12.
    Myatt, L., & Cui, X. (2004). Oxidative stress in the placenta. Histochemistry and Cell Biology, 122(4), 369–382.CrossRefPubMedGoogle Scholar
  13. 13.
    Poston, L. and M.T. Raijmakers( 2004). Trophoblast oxidative stress, antioxidants and pregnancy outcome–a review. Placenta, 25 Suppl A: p. S72-8.Google Scholar
  14. 14.
    Jauniaux, E., et al. (2000). Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. The American Journal of Pathology, 157(6), 2111–2122.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Braekke, K., Harsem, N. K., & Staff, A. C. (2006). Oxidative stress and antioxidant status in fetal circulation in preeclampsia. Pediatric Research, 60(5), 560–564.CrossRefPubMedGoogle Scholar
  16. 16.
    Jackson, B., et al. (2011). Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Human Genomics, 5(4), 283–303.Google Scholar
  17. 17.
    Muzio, G., et al. (2012). Aldehyde dehydrogenases and cell proliferation. Free Radical Biology & Medicine, 52(4), 735–746.CrossRefGoogle Scholar
  18. 18.
    Balber, A. E. (2011). Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine. Stem Cells, 29(4), 570–575.CrossRefPubMedGoogle Scholar
  19. 19.
    Guppy, N., L. Nicholson, and Alison, M. (2011). ABC Transporters, Aldehyde Dehydrogenase, and Adult Stem Cells, in Adult Stem Cells, D.G. Phinney, Editor. Humana Press. p. 181-199.Google Scholar
  20. 20.
    Douville, J., Beaulieu, R., & Balicki, D. (2008). ALDH1 as a Functional Marker of Cancer Stem and Progenitor Cells. Stem Cells and Development, 18(1), 17–26.CrossRefGoogle Scholar
  21. 21.
    Vauchez, K., et al. (2009). Aldehyde dehydrogenase activity identifies a population of human skeletal muscle cells with high myogenic capacities. Molecular Therapy, 17(11), 1948–1958.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Keller, L. H. (2009). Bone marrow-derived aldehyde dehydrogenase-bright stem and progenitor cells for ischemic repair. Congestive Heart Failure, 15(4), 202–206.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen, Y., et al. (2012). Focus on molecules: ALDH1A1: from lens and corneal crystallin to stem cell marker. Experimental Eye Research,. 102(0): p. 105–106.Google Scholar
  24. 24.
    Sondergaard, C. S., et al. (2010). Human cord blood progenitors with high aldehyde dehydrogenase activity improve vascular density in a model of acute myocardial infarction. Journal of Translational Medicine, 8(1), 24.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Januchowski, R., Wojtowicz, K., & Zabel, M. (2013). The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomedicine & Pharmacotherapy, 67(7), 669–680.CrossRefGoogle Scholar
  26. 26.
    Singh, S., et al., Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radical Biology & Medicine, 2013. 56(0): p. 89–101.Google Scholar
  27. 27.
    Liu, H., et al. (2014). A novel combination of homeobox genes is expressed in mesenchymal chorionic stem/stromal cells in first trimester and term pregnancies. Reproductive Sciences, 21(11), 1382–1394.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Abumaree, M. H., et al. (2013). Phenotypic and functional characterization of mesenchymal stem cells from chorionic villi of human term placenta. Stem Cell Reviews, 9(1), 16–31.CrossRefPubMedGoogle Scholar
  29. 29.
    Kusuma, G. D., et al. (2015). Ectopic Bone Formation by Mesenchymal Stem Cells Derived from Human Term Placenta and the Decidua. PloS One, 10(10), e0141246.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kusuma, G. D., et al. (2015). Mesenchymal stem cells reside in a vascular niche in the decidua basalis and are absent in remodelled spiral arterioles. Placenta, 36(3), 312–321.CrossRefPubMedGoogle Scholar
  31. 31.
    Qin, S. Q., et al. (2016) Establishment and characterization of fetal and maternal mesenchymal stem/stromal cell lines from the human term placenta. Placenta. doi: 10.1016/j.placenta.2016.01.018.
  32. 32.
    Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods, 25(4), 402–408.CrossRefPubMedGoogle Scholar
  33. 33.
    Moreb, J. S. (2008). Aldehyde dehydrogenase as a marker for stem cells. Current Stem Cell Research & Therapy, 3(4), 237–246.CrossRefGoogle Scholar
  34. 34.
    Holdsworth-Carson, S. J., et al. (2014). Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues. Molecular Human Reproduction, 20(3), 250–259.CrossRefPubMedGoogle Scholar
  35. 35.
    Dominici, M., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317.CrossRefPubMedGoogle Scholar
  36. 36.
    Parolini, O., et al. (2008). Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells, 26(2), 300–311.CrossRefPubMedGoogle Scholar
  37. 37.
    Fukuchi, Y., et al. (2004). Human Placenta-Derived Cells Have Mesenchymal Stem/Progenitor Cell Potential. Stem Cells, 22(5), 649–658.CrossRefPubMedGoogle Scholar
  38. 38.
    Nazarov, I., et al. (2012). Multipotent stromal stem cells from human placenta demonstrate high therapeutic potential. Stem Cells Translational Medicine, 1(5), 359–372.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhu, Y., et al. (2014). Placental mesenchymal stem cells of fetal and maternal origins demonstrate different therapeutic potentials. Stem Cell Research & Therapy, 5(2), 48.CrossRefGoogle Scholar
  40. 40.
    Kastan, M. B., et al. (1990). Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood, 75(10), 1947–1950.PubMedGoogle Scholar
  41. 41.
    Ginestier, C., et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1(5), 555–567.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Penumatsa, K., et al., (2010) Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors. J Ovarian Res,. 3: p. 28.Google Scholar
  43. 43.
    Rahadiani, N., et al. (2011). Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications. Cancer Science, 102(4), 903–908.CrossRefPubMedGoogle Scholar
  44. 44.
    Dimitrov, R., et al. (2010). First-trimester human decidua contains a population of mesenchymal stem cells. Fertility and Sterility, 93(1), 210–219.CrossRefPubMedGoogle Scholar
  45. 45.
    Psaltis, P. J., et al. (2010). Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. Journal of Cellular Physiology, 223(2), 530–540.PubMedGoogle Scholar
  46. 46.
    Zannettino, A. C., et al. (2008). Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. Journal of Cellular Physiology, 214(2), 413–421.CrossRefPubMedGoogle Scholar
  47. 47.
    Gentry, T., et al. (2007). Simultaneous isolation of human BM hematopoietic, endothelial and mesenchymal progenitor cells by flow sorting based on aldehyde dehydrogenase activity: implications for cell therapy. Cytotherapy, 9(3), 259–274.CrossRefPubMedGoogle Scholar
  48. 48.
    Capoccia, B. J., et al. (2009). Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. Blood, 113(21), 5340–5351.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Povsic, T. J., et al. (2009). Aldehyde dehydrogenase activity allows reliable EPC enumeration in stored peripheral blood samples. Journal of Thrombosis and Thrombolysis, 28(3), 259–265.CrossRefPubMedGoogle Scholar
  50. 50.
    Jean, E., et al. (2011). Aldehyde dehydrogenase activity promotes survival of human muscle precursor cells. Journal of Cellular and Molecular Medicine, 15(1), 119–133.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nagano, M., et al. (2010). Hypoxia responsive mesenchymal stem cells derived from human umbilical cord blood are effective for bone repair. Stem Cells and Development, 19(8), 1195–1210.CrossRefPubMedGoogle Scholar
  52. 52.
    Watt, S. M., et al. (2013). The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. British Medical Bulletin, 108, 25–53.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hess, D. A., et al. (2008). Widespread nonhematopoietic tissue distribution by transplanted human progenitor cells with high aldehyde dehydrogenase activity. Stem Cells, 26(3), 611c620.Google Scholar
  54. 54.
    Burger, P. E., et al. (2009). High aldehyde dehydrogenase activity: a novel functional marker of murine prostate stem/progenitor cells. Stem Cells, 27(9), 2220–2228.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Gina D. Kusuma
    • 1
    • 2
  • Mohamed H. Abumaree
    • 3
  • Mark D. Pertile
    • 4
    • 5
  • Anthony V. Perkins
    • 6
  • Shaun P. Brennecke
    • 1
    • 2
  • Bill Kalionis
    • 1
    • 2
    Email author
  1. 1.Department of Obstetrics and GynaecologyUniversity of Melbourne, Royal Women’s HospitalParkvilleAustralia
  2. 2.Pregnancy Research Centre, Department of Maternal-Fetal MedicineRoyal Women’s HospitalParkvilleAustralia
  3. 3.King Abdullah International Medical Research Center/ King Saud Bin Abdulaziz University for Health Sciences, College of Science and Health ProfessionsKing Abdulaziz Medical City – National Guard Health AffairsRiyadhKingdom of Saudi Arabia
  4. 4.Victorian Clinical Genetics Services, Murdoch Children’s Research InstituteRoyal Children’s HospitalParkvilleAustralia
  5. 5.Department of PaediatricsUniversity of Melbourne, Royal Children’s HospitalParkvilleAustralia
  6. 6.School of Medical Science, Menzies Health Institute QueenslandGriffith UniversitySouthportAustralia

Personalised recommendations