In situ normoxia enhances survival and proliferation rate of human adipose tissue-derived stromal cells without increasing the risk of tumourigenesis

PLoS ONE

Volumn 10, Issue 1, 2015, Pages

  Choi, Jane Ru ^a   Pingguan Murphy, Belinda ^a   Abas, Wan Abu Bakar Wan ^a   Yong, Kar Wey ^a   Poon, Chi Tat ^a   Azmi, Adenan Noor ^a   Omar, Siti Zawiah ^a   Chua, Kien Hui ^b   Xu, Feng ^c   Safwani, Wan Kamarul Zaman Wan ^a  

^a UNIVERSITY OF MALAYA   (Malaysia)

^b DEPARTMENT OF PHARMACOLOGY   (Malaysia)

^c XI'AN JIAOTONG UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

MESSENGER RNA; OXYGEN; TELOMERASE; VASCULOTROPIN; TUMOR SUPPRESSOR PROTEIN; VASCULOTROPIN A;

ADIPOSE TISSUE DERIVED STROMAL CELL; ADULT; ARTICLE; CARCINOGENESIS; CELL ISOLATION; CELL PROLIFERATION; CELL RENEWAL; CELL STRUCTURE; CELL SURVIVAL; CELL VIABILITY; CONTROLLED STUDY; DNA DAMAGE; ENZYME ACTIVITY; FEMALE; GENE EXPRESSION; HUMAN; HUMAN CELL; IN SITU NORMOXIA; OXYGEN CONCENTRATION; OXYGEN TENSION; OXYGENATION; P16 GENE; P21 GENE; P53 GENE; PRB GENE; PROTEIN SECRETION; RISK FACTOR; STROMA CELL; SUBCUTANEOUS FAT; TUMOR SUPPRESSOR GENE; UPREGULATION; ADIPOSE TISSUE; CELL CULTURE; CELL HYPOXIA; CYTOLOGY; GENETICS; MESENCHYMAL STROMA CELL; METABOLISM; PHYSIOLOGY; TELOMERE HOMEOSTASIS;

ADIPOSE TISSUE; ADULT; CARCINOGENESIS; CELL HYPOXIA; CELL PROLIFERATION; CELLS, CULTURED; FEMALE; HUMANS; MESENCHYMAL STROMAL CELLS; OXYGEN; TELOMERASE; TELOMERE HOMEOSTASIS; TUMOR SUPPRESSOR PROTEINS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84956651274     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0115034     Document Type: Article

References (81)

1. Smith A (2006) A glossary for stem-cell biology. Nature 441: 1060-1060. doi: 10.1038/nature04954
2. Doulatov S, Daley GQ (2013) A Stem Cell Perspective on Cellular Engineering. Science 342: 700-702. doi: 10.1126/science.1238363 PMID: 24202165
3. Wagers AJ (2012) The Stem Cell Niche in Regenerative Medicine. Cell Stem Cell 10: 362-369. doi: 10.1016/j.stem.2012.02.018 PMID: 22482502
4. Rubin JP, Marra KG (2013) Adipose stem cell therapy for soft tissue reconstruction. Lancet 382: 1077-1079. doi: 10.1016/S0140-6736(13)61744-4 PMID: 24075037
5. Kolle SF, Fischer-Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, et al. (2013) Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. Lancet 382: 1113-1120. doi: 10.1016/S0140-6736(13)61410-5 PMID: 24075051
6. Schäffler A, Büchler C (2007) Concise Review: Adipose Tissue-Derived Stromal Cells-Basic and Clinical Implications for Novel Cell-Based Therapies. Stem Cells 25: 818-827. doi: 10.1634/stemcells. 2006-0589 PMID: 17420225
7. Crisan M, Casteilla L, Lehr L, Carmona M, Paoloni-Giacobino A, et al. (2008) A Reservoir of Brown Adipocyte Progenitors in Human Skeletal Muscle. Stem Cells 26: 2425-2433. doi: 10.1634/stemcells. 2008-0325 PMID: 18617684
8. Kim JH, Park SH, Park SG, Choi JS, Xia Y, et al. (2011) The pivotal role of reactive oxygen species generation in the hypoxia-induced stimulation of adipose-derived stem cells. Stem Cells Dev 20: 1753-1761. doi: 10.1089/scd.2010.0469 PMID: 21265612
9. Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, et al. (2008) A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks. Circulation Research 102: 77-85. doi: 10.1161/CIRCRESAHA.107.159475 PMID: 17967785
10. Matsumoto A, Matsumoto S, Sowers AL, Koscielniak JW, Trigg NJ, et al. (2005) Absolute oxygen tension (pO2) in murine fatty and muscle tissue as determined by EPR. Magnetic Resonance in Medicine 54: 1530-1535. doi: 10.1002/mrm.20714 PMID: 16276490
11. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, et al. (2008) Reduced Adipose Tissue Oxygenation in Human Obesity: Evidence for Rarefaction, Macrophage Chemotaxis, and Inflammation Without an Angiogenic Response. Diabetes 58: 718-725. doi: 10.2337/db08-1098 PMID: 19074987
12. Chung H-M, Won C-H, Sung J-H (2009) Responses of adipose-derived stem cells during hypoxia- enhanced skin-regenerative potential. Expert Opin Biol Ther 9: 1499-1508. doi: 10.1517/ 14712590903307362 PMID: 19780713
13. Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441: 1075-1079. doi: 10.1038/ nature04957 PMID: 16810242
14. Ivanovic Z (2009) Hypoxia or in situ normoxia: The stem cell paradigm. J Cell Physiol 219: 271-275. doi: 10.1002/jcp.21690 PMID: 19160417
15. Estrada JC, Albo C, Benguría A, Dopazo A, López-Romero P, et al. (2011) Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis. Cell Death and Differentiation 19: 743-755. doi: 10.1038/cdd.2011.172 PMID: 22139129
16. Valorani MG, Montelatici E, Germani A, Biddle A, D0 Alessandro D, et al. (2012) Pre-culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials. Cell Proliferation 45: 225-238. doi: 10.1111/j.1365-2184.2012.00817.x PMID: 22507457
17. Xu Y, Malladi P, Chiou M, Bekerman E, Giaccia AJ, et al. (2007) In vitro expansion of adipose-derived adult stromal cells in hypoxia enhances early chondrogenesis. Tissue Eng 13: 2981-2993. doi: 10. 1089/ten.2007.0050 PMID: 17916040
18. Hung SP, Yang MH, Tseng KF, Lee OK (2013) Hypoxia-induced secretion of TGF-beta1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant 22: 1869-1882. doi: 10.3727/ 096368912X657954 PMID: 23067574
19. Thangarajah H, Vial IN, Chang E, El-Ftesi S, Januszyk M, et al. (2009) IFATS Collection: Adipose Stromal Cells Adopt a Proangiogenic Phenotype Under the Influence of Hypoxia. Stem Cells 27: 266-274. doi: 10.1634/stemcells.2008-0276 PMID: 18974212
20. Kim S, Chaudhry A, Lee I, Frank JA (2013) Effects of Long-Term Hypoxia and Pro-Survival Cocktail in Bone Marrow-Derived Stromal Cell Survival. Stem Cells Dev 20: 20.
21. Crisostomo PR, Wang Y, Markel TA, Wang M, Lahm T, et al. (2008) Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism. American Journal of Physiology-Cell Physiology 294: C675-C682. doi: 10.1152/ajpcell. 00437.2007 PMID: 18234850
22. Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, et al. (2004) Role of Hypoxia-Inducible Factor 1 in Gastric Cancer Cell Growth, Angiogenesis, and Vessel Maturation. JNCI Journal of the National Cancer Institute 96: 946-956. doi: 10.1093/jnci/djh168
23. Hanahan D, Weinberg RA (2011) Hallmarks of Cancer: The Next Generation. Cell 144: 646-674. doi: 10.1016/j.cell.2011.02.013 PMID: 21376230
24. Valorani MG, Germani A, Otto WR, Harper L, Biddle A, et al. (2010) Hypoxia increases Sca-1/CD44 coexpression in murine mesenchymal stem cells and enhances their adipogenic differentiation potential. Cell Tissue Res 341: 111-120. doi: 10.1007/s00441-010-0982-8 PMID: 20496083
25. Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, et al. (2009) Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen 17: 540-547. doi: 10.1111/j.1524-475X.2009.00499.x PMID: 19614919
26. Choi JR, Pingguan-Murphy B, Wan Abas WAB, Noor Azmi MA, Omar SZ, et al. (2014) Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells. Biochemical and Biophysical Research Communications 448: 218-224. doi: 10.1016/j.bbrc. 2014.04.096 PMID: 24785372
27. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, et al. (2009) Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 69: 5331-5339. doi: 10.1158/0008-5472.CAN-08-4630 PMID: 19509230
28. Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, et al. (2005) Spontaneous human adult stem cell transformation. Cancer Res 65: 3035-3039. PMID: 15833829
29. Barkholt L, Flory E, Jekerle V, Lucas-Samuel S, Ahnert P, et al. (2013) Risk of tumorigenicity in mesenchymal stromal cell-based therapies-Bridging scientific observations and regulatory viewpoints. Cytotherapy 15: 753-759. doi: 10.1016/j.jcyt.2013.03.005 PMID: 23602595
30. Pan Q, Fouraschen SM, de Ruiter PE, Dinjens WN, Kwekkeboom J, et al. (2013) Detection of spontaneous tumorigenic transformation during culture expansion of human mesenchymal stromal cells. Experimental Biology and Medicine: 1535370213506802.
31. Ben-David U, Mayshar Y, Benvenisty N (2011) Large-scale analysis reveals acquisition of lineagespecific chromosomal aberrations in human adult stem cells. Cell Stem Cell 9: 97-102. doi: 10.1016/j. stem.2011.06.013 PMID: 21816361
32. Prockop DJ, Keating A (2012) Relearning the Lessons of Genomic Stability of Human Cells During Expansion in Culture: Implications for Clinical Research. STEM CELLS 30: 1051-1052. doi: 10.1002/ stem.1103 PMID: 22495826
33. Wan Kamarul Zaman WS, Makpol S, Sathapan S, Chua KH (2014) Long-term in vitro expansion of human adipose-derived stem cells showed low risk of tumourigenicity. Journal of Tissue Engineering and Regenerative Medicine 8: 67-76. doi: 10.1002/term.1501
34. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, et al. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315-317.
35. Mitchell JB, McIntosh K, Zvonic S, Garrett S, Floyd ZE, et al. (2006) Immunophenotype of Human Adipose-Derived Cells: Temporal Changes in Stromal-Associated and Stem Cell-Associated Markers. Stem Cells 24: 376-85. doi: 10.1634/stemcells.2005-0234
36. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A (2014) Concise Review: Evidence for CD34 as a Common Marker for Diverse Progenitors. Stem Cells 32: 1380-1389. doi: 10.1002/stem.1661 PMID: 24497003
37. Hsiao ST, Lokmic Z, Peshavariya H, Abberton KM, Dusting GJ, et al. (2013) Hypoxic conditioning enhances the angiogenic paracrine activity of human adipose-derived stem cells. Stem cells and development 22: 1614-1623. doi: 10.1089/scd.2012.0602 PMID: 23282141
38. Sheehy EJ, Buckley CT, Kelly DJ (2012) Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells. Biochemical and biophysical research communications 417: 305-310. doi: 10.1016/j.bbrc.2011.11.105 PMID: 22155244
39. Dos Santos F, Andrade PZ, Boura JS, Abecasis MM, Da Silva CL, et al. (2010) Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. Journal of cellular physiology 223: 27-35. PMID: 20020504
40. Malladi P, Xu Y, Chiou M, Giaccia AJ, Longaker MT (2006) Effect of reduced oxygen tension on chondrogenesis and osteogenesis in adipose-derived mesenchymal cells. American Journal of Physiology-Cell Physiology 290: C1139-C1146. doi: 10.1152/ajpcell.00415.2005 PMID: 16291817
41. Charbord P, Casteilla L (2011) [Human mesenchymal stem cell biology]. Med Sci (Paris) 27: 261-267. doi: 10.1051/medsci/2011273261
42. Wagegg M, Gaber T, Lohanatha FL, Hahne M, Strehl C, et al. (2012) Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PLoS One 7: e46483. doi: 10.1371/journal.pone.0046483 PMID: 23029528
43. Berniakovich I, Giorgio M (2013) Low Oxygen Tension Maintains Multipotency, Whereas Normoxia Increases Differentiation of Mouse Bone Marrow Stromal Cells. International Journal of Molecular Sciences 14: 2119-2134. doi: 10.3390/ijms14012119 PMID: 23340651
44. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, et al. (2005) Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 33: 1402-1416. doi: 10.1016/j.exphem.2005.07.003 PMID: 16263424
45. Grayson WL, Zhao F, Bunnell B, Ma T (2007) Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochemical and Biophysical Research Communications 358: 948-953. doi: 10.1016/j.bbrc.2007.05.054 PMID: 17521616
46. Ahn HJ, Lee WJ, Kwack K, Kwon YD (2009) FGF2 stimulates the proliferation of human mesenchymal stem cells through the transient activation of JNK signaling. FEBS Lett 583: 2922-2926. doi: 10.1016/j. febslet.2009.07.056 PMID: 19664626
47. Chen G, Shi X, Sun C, Li M, Zhou Q, et al. (2013) VEGF-mediated proliferation of human adipose tis-sue-derived stem cells. PLoS One 8: e73673. doi: 10.1371/journal.pone.0073673 PMID: 24098328
48. Tamama K, Kawasaki H, Kerpedjieva SS, Guan J, Ganju RK, et al. (2011) Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem 112: 804-817. doi: 10.1002/jcb.22961 PMID: 21328454
49. Sheehy EJ, Buckley CT, Kelly DJ (2012) Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells. Biochem Biophys Res Commun 417: 305-310. doi: 10.1016/j.bbrc.2011.11.105 PMID: 22155244
50. Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12: 440-450. doi: 10.1016/j.molmed.2006.07.007 PMID: 16899408
51. Plotkin JB, Nowak MA (2002) The Different Effects of Apoptosis and DNA Repair on Tumorigenesis. Journal of Theoretical Biology 214: 453-467. doi: 10.1006/jtbi.2001.2471 PMID: 11846602
52. Pilgaard L, Lund P, Duroux M, Lockstone H, Taylor J, et al. (2009) Transcriptional signature of human adipose tissue-derived stem cells (hASCs) preconditioned for chondrogenesis in hypoxic conditions. Experimental Cell Research 315: 1937-1952. doi: 10.1016/j.yexcr.2009.01.020 PMID: 19331821
53. Rehman J (2004) Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells. Circulation 109: 1292-1298. doi: 10.1161/01.CIR.0000121425.42966.F1 PMID: 14993122
54. Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A (2010) Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche. Cell Stem Cell 7: 150-161. doi: 10.1016/j.stem.2010.07.007 PMID: 20682444
55. Stubbs SL, Hsiao ST-F, Peshavariya HM, Lim SY, Dusting GJ, et al. (2012) Hypoxic Preconditioning Enhances Survival of Human Adipose-Derived Stem Cells and Conditions Endothelial Cells In Vitro. Stem Cells and Development 21: 1887-1896. doi: 10.1089/scd.2011.0289 PMID: 22165914
56. Shih-Chieh H, Radhika RP, Shu-Ching H, Cecelia S, Sy-Chi C, et al. (2007) Short-Term Exposure of Multipotent Stromal Cells to Low Oxygen Increases Their Expression of CX3CR1 and CXCR4 and Their Engraftment In Vivo. PLoS ONE 2.
57. Yang D-C, Yang M-H, Tsai C-C, Huang T-F, Chen Y-H, et al. (2011) Hypoxia Inhibits Osteogenesis in Human Mesenchymal Stem Cells through Direct Regulation of RUNX2 by TWIST. PLoS ONE 6: e23965. doi: 10.1371/journal.pone.0023965 PMID: 21931630
58. Wagegg M, Gaber T, Lohanatha FL, Hahne M, Strehl C, et al. (2012) Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner. PLoS ONE 7: e46483. doi: 10.1371/journal.pone.0046483 PMID: 23029528
59. Ahn H-J, Lee W-J, Kwack K, Kwon YD (2009) FGF2 stimulates the proliferation of human mesenchymal stem cells through the transient activation of JNK signaling. FEBS Letters 583: 2922-2926. doi: 10.1016/j.febslet.2009.07.056 PMID: 19664626
60. Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9: 777-794. doi: 10.1111/j.1582-4934.2005.tb00379. x PMID: 16364190
61. Eiselleova L, Matulka K, Kriz V, Kunova M, Schmidtova Z, et al. (2009) A complex role for FGF-2 in selfrenewal, survival, and adhesion of human embryonic stem cells. Stem Cells 27: 1847-1857. doi: 10. 1002/stem.128 PMID: 19544431
62. Wan Kamarul Zaman WS, Makpol S, Sathapan S, Chua KH (2012) Long-term in vitro expansion of human adipose-derived stem cells showed low risk of tumourigenicity. Journal of Tissue Engineering and Regenerative Medicine 8: 67-76. doi: 10.1002/term.1501
63. Pelicci PG (2004) Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? J Clin Invest 113: 4-7. doi: 10.1172/JCI200420750 PMID: 14702099
64. Lilian C-N, Magda Carolina S-C, Sandra Rocío R-C (2010) The Dual Role of Senescence in Tumorigenesis. Sociedad Chilena de Anatomía 28.
65. Solozobova V, Rolletschek A, Blattner C (2009) Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage. BMC Cell Biology 10: 46. doi: 10.1186/1471-2121-10-46 PMID: 19534768
66. Inoue K, Kurabayashi A, Shuin T, Ohtsuki Y, Furihata M (2012) Overexpression of p53 protein in human tumors. Medical Molecular Morphology 45: 115-123. doi: 10.1007/s00795-012-0575-6 PMID: 23001293
67. Kikuchi S, Nishimura R, Osako T, Okumura Y, Nishiyama Y, et al. (2013) Definition of p53 overexpression and its association with the clinicopathological features in luminal/HER2-negative breast cancer. Anticancer Res 33: 3891-3897. PMID: 24023325
68. Offer H, Erez N, Zurer I, Tang X, Milyavsky M, et al. (2002) The onset of p53-dependent DNA repair or apoptosis is determined by the level of accumulated damaged DNA. Carcinogenesis 23: 1025-1032. doi: 10.1093/carcin/23.6.1025 PMID: 12082025
69. Tsai CC, Chen YJ, Yew TL, Chen LL, Wang JY, et al. (2010) Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. Blood 117: 459-469. doi: 10.1182/blood-2010-05-287508 PMID: 20952688
70. Jin Y, Kato T, Furu M, Nasu A, Kajita Y, et al. (2010) Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase. Biochem Biophys Res Commun 391: 1471-1476. doi: 10.1016/j.bbrc.2009.12.096 PMID: 20034468
71. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, et al. (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434: 907-913. doi: 10.1038/nature03485 PMID: 15829965
72. Gomez DE, Armando RG, Farina HG, Menna PL, Cerrudo CS, et al. (2012) Telomere structure and telomerase in health and disease (review). Int J Oncol 41: 1561-1569. doi: 10.3892/ijo.2012.1611 PMID: 22941386
73. Blasco MaA (2003) Telomeres and cancer: a tale with many endings. Current Opinion in Genetics & Development 13: 70-76. doi: 10.1016/S0959-437X(02)00011-4
74. Artandi SE, DePinho RA (2010) Telomeres and telomerase in cancer. Carcinogenesis 31: 9-18. doi: 10.1093/carcin/bgp268 PMID: 19887512
75. Stewart SA, Weinberg RA (2002) Senescence: does it all happen at the ends? Oncogene 21: 627-630. doi: 10.1038/sj.onc.1205062 PMID: 11850788
76. Stampfer MR, Garbe J, Nijjar T, Wigington D, Swisshelm K, et al. (2003) Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene 22: 5238-5251. doi: 10.1038/sj.onc.1206667 PMID: 12917625
77. Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66: 407-425. doi: 10.1128/MMBR.66.3.407-425.2002 PMID: 12208997
78. Murofushi Y, Nagano S, Kamizono J, Takahashi T, Fujiwara H, et al. (2006) Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: a promising implication of telomerase-dependent targeted cancer gene therapy. Int J Oncol 29: 681-688. PMID: 16865285
79. Dos Santos F, Andrade PZ, Boura JS, Abecasis MM, da Silva CL, et al. (2010) Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. J Cell Physiol 223: 27-35. PMID: 20020504
80. Yanada S, Ochi M, Kojima K, Sharman P, Yasunaga Y, et al. (2006) Possibility of selection of chondrogenic progenitor cells by telomere length in FGF-2-expanded mesenchymal stromal cells. Cell Prolif 39: 575-584. doi: 10.1111/j.1365-2184.2006.00397.x PMID: 17109640
81. Buchheiser A, Houben AP, Bosch J, Marbach J, Liedtke S, et al. (2012) Oxygen tension modifies the 'stemness' of human cord blood-derived stem cells. Cytotherapy 14: 967- 982. doi: 10.3109/14653249. 2012.671518 PMID: 22494073