Aging of mesenchymal stem cell in vitro

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Abstract

Background

A hot new topic in medical treatment is the use of mesenchymal stem cells (MSC) in therapy. The low frequency of this subpopulation of stem cells in bone marrow (BM) necessitates their in vitro expansion prior to clinical use. We evaluated the effect of long term culture on the senescence of these cells.

Results

The mean long term culture was 118 days and the mean passage number was 9. The average number of PD decreased from 7.7 to 1.2 in the 10th passage. The mean telomere length decreased from 9.19 Kbp to 8.7 kbp in the 9th passage. Differentiation potential dropped from the 6th passage on. The culture's morphological abnormalities were typical of the Hayflick model of cellular aging.

Conclusion

We believe that MSC enter senescence almost undetectably from the moment of in vitro culturing. Simultaneously these cells are losing their stem cell characteristics. Therefore, it is much better to consider them for cell and gene therapy early on.

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Most cited references 19

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Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.

Melissa A Baxter, Robert Wynn, Simon Jowitt … (2004)

Human marrow stromal cells (MSCs) can be isolated from bone marrow and differentiate into multiple tissues in vitro and in vivo. These properties make them promising tools in cell and gene therapy. The lack of a specific MSC marker and the low frequency of MSCs in bone marrow necessitate their isolation by in vitro expansion prior to clinical use. This may severely reduce MSC proliferative capacity to the point that the residual proliferative potential is insufficient to maintain long-term tissue regeneration upon reinfusion. In this study we determined the effect of in vitro expansion on the replicative capacity of MSCs by correlating their rate of telomere loss during in vitro expansion with their behavior in vivo. We report that even protocols that involve minimal expansion induce a rapid aging of MSCs, with losses equivalent to about half their total replicative lifespan.

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Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate.

C. M. DiGirolamo, D. Stokes, D Colter … (1999)

Marrow stromal cells (MSCs) were isolated from bone marrow obtained by aspirates of the iliac crest of normal volunteers. The cells were isolated by their adherence to plastic and then passed in culture. Some of the samples expanded through over 15 cell doublings from the time frozen stocks were prepared. Others ceased replicating after about four cell doublings. The replicative potential of the cells in culture was best predicted by a simple colony-forming assay in which samples from early passages were plated at low densities of about 10 cells per cm2. Samples with high colony-forming efficiency exhibited the greatest replicative potential. The colonies obtained by plating early passage cells at low density varied in size and morphology. The large colonies readily differentiated into osteoblasts and adipocytes when incubated in the appropriate medium. As samples were expanded in culture and approached senescence, they retained their ability to differentiate into osteoblasts. However, the cells failed to differentiate into adipocytes. The loss of multipotentiality following serial passage in culture may have important implications for the use of expanded MSCs for cell and gene therapy.

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Spontaneous human adult stem cell transformation.

Daniel Rubio, Javier García-Castro, María C. Martín … (2005)

Human adult stem cells are being evaluated widely for various therapeutic approaches. Several recent clinical trials have reported their safety, showing them to be highly resistant to transformation. The clear similarities between stem cell and cancer stem cell genetic programs are nonetheless the basis of a recent proposal that some cancer stem cells could derive from human adult stem cells. Here we show that although they can be managed safely during the standard ex vivo expansion period (6-8 weeks), human mesenchymal stem cells can undergo spontaneous transformation following long-term in vitro culture (4-5 months). This is the first report of spontaneous transformation of human adult stem cells, supporting the hypothesis of cancer stem cell origin. Our findings indicate the importance of biosafety studies of mesenchymal stem cell biology to efficiently exploit their full clinical therapeutic potential.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Cell Biol

Title: BMC Cell Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2121

Publication date Collection: 2006

Publication date (Electronic): 10 March 2006

Volume: 7

Page: 14

Affiliations

[1 ]Hematology-Oncology & BMT Research Center, Shariati Hospital, Tehran University of Medical Sciences, Iran

[2 ]Immunogenetics lab, Dept. of Immunology, College of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Article

Publisher ID: 1471-2121-7-14

DOI: 10.1186/1471-2121-7-14

PMC ID: 1435883

PubMed ID: 16529651

SO-VID: 5d2488be-4e00-4a75-ade5-86506b0d32b9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Aging of mesenchymal stem cell in vitro

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Abstract

Background

Results

Conclusion

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Stress signalling in stem cells

Most cited references 19

Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.

Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate.

Spontaneous human adult stem cell transformation.

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