Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells
Abstract
Changes in oxygen concentrations affect many of the innate characteristics of stem and progenitor cells. Human mesenchymal stem cells (hMSCs) were maintained under hypoxic atmospheres (2% O(2)) for up to seven in vitro passages. This resulted in approximately 30-fold higher hMSC expansion over 6 weeks without loss of multi-lineage differentiation capabilities. Under hypoxia, hMSCs maintained their growth-rates even after reaching confluence, resulting in the formation of multiple cell layers. Hypoxic hMSCs also displayed differences in the cell and nuclear morphologies as well as enhanced ECM formation and organization. These changes in cellular characteristics were accompanied by higher mRNA levels of Oct-4 and HIF-2alpha, as well as increased expression levels of connexin-43, a protein used in gap junction formation. The results from this study demonstrated that oxygen concentrations affected many aspects of stem-cell physiology, including growth and in vitro development, and may be a critical parameter during expansion and differentiation.
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A large number of studies demonstrated that MSCs cultured in hypoxia exhibit higher rates of proliferation and better retain their stem cell properties.
“A large number of studies demonstrated that MSCs cultured in hypoxia exhibit higher rates of proliferation and better retain their stem cell properties [25, 30–33].”
From Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells (2018) · cites this paper as [30]
Cites
Multilineage potential of adult human mesenchymal stem cells
Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., & Marshak, D. R. (1999) · Science · doi:10.1126/science.284.5411.143 · Cited by 21,052 · see citing works
Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro
Jaiswal, N., Haynesworth, S. E., Caplan, A. I., & Bruder, S. P. (1997) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(199702)64:2 · Cited by 2,547 · see citing works
Sekiya, I., Larson, B. L., Smith, J. R., Pochampally, R. R., Cui, J., & Prockop, D. J. (2002) · Stem Cells · doi:10.1634/stemcells.20-6-530 · Cited by 943 · see citing works
Low O 2 tensions and the prevention of differentiation of hES cells
Ezashi, T., Das, P., & Roberts, R. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501283102 · Cited by 804 · see citing works
D’Ippolito, G., Diabira, S., Howard, G. A., Meneï, P., Roos, B. A., & Schiller, P. C. (2004) · Journal of Cell Science · doi:10.1242/jcs.01103 · Cited by 665 · see citing works
Lennon, D. P., Edmison, J. M., & Caplan, A. I. (2001) · Journal of Cellular Physiology · doi:10.1002/jcp.1081 · Cited by 425 · see citing works
Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs
Grayson, W. L., Zhao, F., Izadpanah, R., Bunnell, B. A., & Ma, T. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20571 · Cited by 409 · see citing works
Self-citationAdult human mesenchymal stem cell as a target for neoplastic transformation
Serakinci, N., Guldberg, P., Burns, J. S., Abdallah, B., Schrødder, H., Jensen, T., & Kassem, M. (2004) · Oncogene · doi:10.1038/sj.onc.1207651 · Cited by 350 · see citing works
Robins, J. C., Akeno, N., Mukherjee, A., Dalal, R. R., Aronow, B. J., Koopman, P. A., & Clemens, T. L. (2005) · Bone · doi:10.1016/j.bone.2005.04.040 · Cited by 317 · see citing works
Hypoxia Promotes Murine Bone‐Marrow‐Derived Stromal Cell Migration and Tube Formation
Annabi, B., Lee, Y., Turcotte, S., Naud, E., Desrosiers, R. R., Champagne, M. A., Eliopoulos, N., Galipeau, J., & Béliveau, R. (2003) · Stem Cells · doi:10.1634/stemcells.21-3-337 · Cited by 302 · see citing works
Malladi, P., Xu, Y., Chiou, M., Giaccia, A. J., & Longaker, M. T. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00415.2005 · Cited by 301 · see citing works
Oxygen in the Cultivation of Stem Cells
CSETE, M. E. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1334.001 · Cited by 269 · see citing works
Influence of oxygen on the proliferation and metabolism of adipose derived adult stem cells
Wang, D. W., Fermor, B., Gimble, J. M., et al. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20324 · Cited by 219 · see citing works
Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions
Ren, H., Cao, Y., Zhao, Q., Li, J., Zhou, C.-X., Liao, L., Jia, M., Zhao, Q., Cai, H., Han, Z., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.05.169 · Cited by 201 · see citing works
Induction of Adipocyte‐Like Phenotype in Human Mesenchymal Stem Cells by Hypoxia
Fink, T., Abildtrup, L. A., Fogd, K., Abdallah, B. M., Kassem, M. S., Ebbesen, P., & Zachar, V. (2004) · Stem Cells · doi:10.1634/stemcells.2004-0038 · Cited by 179 · see citing works
Wiblin, A. E., Cui, W., Clark, A. J., & Bickmore, W. A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02500 · Cited by 164 · see citing works
Lee, J.-H., & Kemp, D. M. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.01.038 · Cited by 158 · see citing works
Human Mesenchymal Stem Cells Tissue Development in 3D PET Matrices
Grayson, W. L., Ma, T., & Bunnell, B. A. (2004) · Biotechnology Progress · doi:10.1021/bp034296z · Cited by 150 · see citing works
Self-citationEffects of Hypoxia on the Proliferation and Differentiation of NSCs
Zhu, L., Wu, L., Yew, D. T. W., & Fan, M. (2005) · Molecular Neurobiology · doi:10.1385/mn:31:1-3:231 · Cited by 145 · see citing works
Baksh, D., Davies, J. E., & Zandstra, P. W. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(03)00106-1 · Cited by 139 · see citing works
Ivanović, Z., Sbarba, P. D., Trimoreau, F., Faucher, J., & Praloran, V. (2000) · Transfusion · doi:10.1046/j.1537-2995.2000.40121482.x · Cited by 127 · see citing works
Cheng, A., Tang, H., Cai, J., Zhu, M., Zhang, X., Rao, M. S., & Mattson, M. P. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.04.031 · Cited by 120 · see citing works
Cell-to-cell interactions in bone
Stains, J. P., & Civitelli, R. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.078 · Cited by 118 · see citing works
Ignored Hallmarks of Carcinogenesis: Stem Cells and Cell‐Cell Communication
Trosko, J. E., CHANG, C., Upham, B. L., et al. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1322.023 · Cited by 116 · see citing works
Ivanović, Z., Bartolozzi, Bernabei, Cipolleschi, Rovida, E., Milenković, Praloran, & Sbarba (2000) · British Journal of Haematology · doi:10.1046/j.1365-2141.2000.01842.x · Cited by 106 · see citing works
Presence of Functional Gap Junctions in Human Embryonic Stem Cells
Wong, R. C. B., Pébay, A., Nguyen, L. T. V., et al. (2004) · Stem Cells · doi:10.1634/stemcells.22-6-883 · Cited by 93 · see citing works
Zhang, W., Green, C. R., & Stott, N. S. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10168 · Cited by 67 · see citing works
Effect of the neuropeptide substance P on the rat bone marrow-derived osteogenic cells in vitro
Adamus, M., & browski, Z. J. D. (2001) · Journal of Cellular Biochemistry · doi:10.1002/1097-4644(20010601)81:3 · Cited by 54 · see citing works
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Cesarz, Z., & Tamama, K. (2016) · Stem Cells International · doi:10.1155/2016/9176357 · Cited by 475 · see citing works
Lee, E. Y., Xia, Y., Kim, W., Kim, M. H., Kim, T. H., Kim, K. J., Park, B., & Sung, J. (2009) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2009.00499.x · Cited by 423 · see citing works
Holzwarth, C., Vaegler, M., Gieseke, F., Pfister, S. M., Handgretinger, R., Kerst, G., & Müller, I. (2010) · BMC Cell Biology · doi:10.1186/1471-2121-11-11 · Cited by 314 · see citing works
Das, R., Jahr, H., van Osch, G. J. V. M., & Farrell, E. (2010) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2009.0296 · Cited by 297 · see citing works
Chen, L., Xu, Y., Zhao, J., Zhang, Z., Yang, R., Xie, J., Liu, X., & Qi, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096161 · Cited by 251 · see citing works
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Antebi, B., Rodriguez, L. A., Walker, K. P., Asher, A. M., Kamucheka, R. M., Alvarado, L., Mohammadipoor, A., & Cancio, L. C. (2018) · Stem Cell Research & Therapy · doi:10.1186/s13287-018-1007-x · Cited by 137 · see citing works
Boyette, L. B., Creasey, O. A., Guzik, L., Lozito, T., & Tuan, R. S. (2014) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0079 · Cited by 121 · see citing works
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Nauta, A., Gurtner, G., & Longaker, M. (2011) · Oral Diseases · doi:10.1111/j.1601-0825.2011.01787.x · Cited by 78 · see citing works
Choi, J. R., Pingguan-Murphy, B., Wan Abas, W. A. B., Yong, K. W., Poon, C. T., Noor Azmi, M. A., Omar, S. Z., Chua, K. H., Xu, F., & Wan Safwani, W. K. Z. (2015) · PLOS ONE · doi:10.1371/journal.pone.0115034 · Cited by 63 · see citing works
- Authors
- Grayson, W. L., Zhao, F., Bunnell, B., & Ma, T.
- Affiliations
- Florida A&M University - Florida State University College of Engineering (US)
- Tulane University (US)
- Corresponding author
- Ma, Teng
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 358
- Issue
- 3
- Pages
- 948-953
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2155243243
- Cited by
- 521
- References
- 28
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 20 · 2023: 20 · 2022: 24 · 2021: 19 · 2020: 26 · 2019: 22 · 2018: 17 · 2017: 44 · 2016: 42 · 2015: 37 · 2014: 34 · 2013: 47 · 2012: 50
- FWCI
- 11.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- hypoxia, human mesenchymal stem cells, cell proliferation, multilineage differentiation, extracellular matrix synthesis, Oct4, HIF-2α, connexin 43, gap junctions, cell morphology, nuclear morphology, oxygen concentration, stem cell expansion
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Hypoxia, Bone Marrow Cells, Cell Adhesion, Cell Differentiation, Cell Nucleus, Gene Expression Regulation, Humans, Kinetics, Microscopy, Phase-Contrast, RNA, Messenger, Microscopy, Confocal, Cell Proliferation, Octamer Transcription Factor-3, Basic Helix-Loop-Helix Proteins, Mesenchymal Stem Cells
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