Long-term in Vitro Expansion Alters the Biology of Adult Mesenchymal Stem Cells

Overview

Journal Cancer Res

Specialty Oncology

Date 2008 Jun 4

PMID 18519682

Citations 139

Authors

Reza Izadpanah

Deepak Kaushal

Christopher Kriedt

Fern Tsien

Bindiya Patel

Jason Dufour

Bruce A Bunnell

Affiliations

Soon will be listed here.

Abstract

Mesenchymal stem cells (MSC) derived from bone marrow stem cells (BMSC) and adipose tissue stem cells (ASC) of humans and rhesus macaques were evaluated for their cell cycle properties during protracted culture in vitro. Human ASCs (hASC) and rhesus BMSCs (rBMSC) underwent significantly more total population doublings than human BMSCs (hBMSC) and rhesus ASCs (rASC). The cell cycle profile of all MSCs was altered as cultures aged. hMSCs underwent an increase in the frequency of cells in the S phase at P20 and P30. However, rhesus MSCs from both sources developed a distinct polyploid population of cells at P20, which progressed to aneuploidy by P30. Karyotype analysis of MSCs revealed the development of tetraploid or aneuploid karyotypes in the rhesus cells at P20 or P30. Analysis of the transcriptome of the MSCs from early and late passages revealed significant alterations in the patterns of gene expression (8.8% of the genes were differentially expressed in hBMSCs versus hASCs, and 5.5% in rBMSCs versus rASCs). Gene expression changes were much less evident within the same cell type as aging occurred (0.7% in hMSCs and 0.9% in rMSC). Gene ontology analysis showed that functions involved in protein catabolism and regulation of pol II transcription were overrepresented in rASCs, whereas the regulation of I kappa B/nuclear factor-kappaB cascade were overrepresented in hBMSCs. Functional analysis of genes that were differentially expressed in rASCs and hBMSCs revealed that pathways involved in cell cycle, cell cycle checkpoints, protein-ubiquitination, and apoptosis were altered.

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References

Toma C, Pittenger M, Cahill K, Byrne B, Kessler P . Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105(1):93-8. DOI: 10.1161/hc0102.101442. View

Kayo T, Allison D, Weindruch R, Prolla T . Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A. 2001; 98(9):5093-8. PMC: 33169. DOI: 10.1073/pnas.081061898. View

Miura Y, Miura M, Gronthos S, Allen M, Cao C, Uveges T . Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis. Proc Natl Acad Sci U S A. 2005; 102(39):14022-7. PMC: 1236524. DOI: 10.1073/pnas.0409397102. View

Woodbury D, Reynolds K, Black I . Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res. 2002; 69(6):908-17. DOI: 10.1002/jnr.10365. View

Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C . A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-7. PMC: 40985. DOI: 10.1073/pnas.92.20.9363. View

Borel F, Lohez O, Lacroix F, Margolis R . Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells. Proc Natl Acad Sci U S A. 2002; 99(15):9819-24. PMC: 125028. DOI: 10.1073/pnas.152205299. View

Li C, Wong W . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A. 2001; 98(1):31-6. PMC: 14539. DOI: 10.1073/pnas.98.1.31. View

Fortunel N, Otu H, Ng H, Chen J, Mu X, Chevassut T . Comment on " 'Stemness': transcriptional profiling of embryonic and adult stem cells" and "a stem cell molecular signature". Science. 2003; 302(5644):393. DOI: 10.1126/science.1086384. View

Kern S, Eichler H, Stoeve J, Kluter H, Bieback K . Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006; 24(5):1294-301. DOI: 10.1634/stemcells.2005-0342. View

10.

Caceres M, Lachuer J, Zapala M, Redmond J, Kudo L, Geschwind D . Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci U S A. 2003; 100(22):13030-5. PMC: 240739. DOI: 10.1073/pnas.2135499100. View

11.

Fujiyama A, Watanabe H, Toyoda A, Taylor T, Itoh T, Tsai S . Construction and analysis of a human-chimpanzee comparative clone map. Science. 2002; 295(5552):131-4. DOI: 10.1126/science.1065199. View

12.

Fujiwara T, Bandi M, Nitta M, Ivanova E, Bronson R, Pellman D . Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005; 437(7061):1043-7. DOI: 10.1038/nature04217. View

13.

Duesberg P, Li R . Multistep carcinogenesis: a chain reaction of aneuploidizations. Cell Cycle. 2003; 2(3):202-10. View

14.

Uddin M, Wildman D, Liu G, Xu W, Johnson R, Hof P . Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc Natl Acad Sci U S A. 2004; 101(9):2957-62. PMC: 365727. DOI: 10.1073/pnas.0308725100. View

15.

Dillman 3rd J, Phillips C . Comparison of non-human primate and human whole blood tissue gene expression profiles. Toxicol Sci. 2005; 87(1):306-14. DOI: 10.1093/toxsci/kfi243. View

16.

Blackburn E . Switching and signaling at the telomere. Cell. 2001; 106(6):661-73. DOI: 10.1016/s0092-8674(01)00492-5. View

17.

Myung K, Datta A, Kolodner R . Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell. 2001; 104(3):397-408. DOI: 10.1016/s0092-8674(01)00227-6. View

18.

Jiang Y, Jahagirdar B, Reinhardt R, Schwartz R, Keene C, Ortiz-Gonzalez X . Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002; 418(6893):41-9. DOI: 10.1038/nature00870. View

19.

Prockop D . Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997; 276(5309):71-4. DOI: 10.1126/science.276.5309.71. View

20.

Rubio D, Garcia-Castro J, Martin M, De La Fuente R, Cigudosa J, Lloyd A . Spontaneous human adult stem cell transformation. Cancer Res. 2005; 65(8):3035-9. DOI: 10.1158/0008-5472.CAN-04-4194. View