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Long-term In vitro Expansion Alters the Biology of Adult Mesenchymal Stem Cells

Divisions of ¹ Gene Therapy, ² Bacteriology and Parasitology, and ³ Veterinary Medicine, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana; ⁴ Department of Human Genetics, Louisiana State University Health Sciences Center; and Department of ⁵ Pharmacology and ⁶ Center for Gene Therapy, School of Medicine, Tulane University, New Orleans, Louisiana

Requests for reprints: Bruce A. Bunnell, Center for Gene Therapy, Department of Pharmacology, Division of Gene Therapy, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433. Phone: 985-871-6594; Fax: 985-871-6564; E-mail: bbunnell{at}tulane.edu.

Key Words: mesenchymal stem cells • cell cycle • transcriptome • pathway analysis • gene ontology

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 IB/nuclear factor-B 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. [Cancer Res 2008;68(11):4229–38]

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