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3D microtissue formation of undifferentiated bone marrow mesenchymal stem cells leads to elevated apoptosis


Kelm, J M; Breitbach, M; Fischer, G; Odermatt, B; Agarkova, I; Fleischmann, B K; Hoerstrup, S P (2012). 3D microtissue formation of undifferentiated bone marrow mesenchymal stem cells leads to elevated apoptosis. Tissue Engineering. Part A, 18(7/8):online.

Abstract

Current implantation formats to deliver bone marrow-derived mesenchymal stem cells (MSCs) to the site of myocardial injury resulted only in limited cell retention and integration. As an alternative concept to single cell transplantation, we investigated the fate of cell tracker-labeled syngenic rat MSC microtissue implants, injected into the scar area in a chronic rat myocardial infarction model. Analysis of the explants after 2 and 7 days revealed substantial amounts of the cell tracker within the infarct region. However, the signal was associated with the extracellular matrix rather than with viable implanted cells. Following these results, we systematically evaluated the behavior of MSCs derived from mouse, rat and human origin in the microtissue format in vitro. We found that MSC-composed microtissues of all three species displayed highly elevated levels of apoptotic activity and cell death. This effect could be attenuated by initiating osteogenic differentiation during the tissue formation process. We conclude that MSCs used for tissue regeneration undergo apoptosis in their new environment unless they get appropriate signals for differentiation that permit sustained survival. These findings may explain the limited cellular regeneration potential in current MSC-based clinical trials and may change therapeutic strategies away from pure, un-modulated cell delivery concepts.

Current implantation formats to deliver bone marrow-derived mesenchymal stem cells (MSCs) to the site of myocardial injury resulted only in limited cell retention and integration. As an alternative concept to single cell transplantation, we investigated the fate of cell tracker-labeled syngenic rat MSC microtissue implants, injected into the scar area in a chronic rat myocardial infarction model. Analysis of the explants after 2 and 7 days revealed substantial amounts of the cell tracker within the infarct region. However, the signal was associated with the extracellular matrix rather than with viable implanted cells. Following these results, we systematically evaluated the behavior of MSCs derived from mouse, rat and human origin in the microtissue format in vitro. We found that MSC-composed microtissues of all three species displayed highly elevated levels of apoptotic activity and cell death. This effect could be attenuated by initiating osteogenic differentiation during the tissue formation process. We conclude that MSCs used for tissue regeneration undergo apoptosis in their new environment unless they get appropriate signals for differentiation that permit sustained survival. These findings may explain the limited cellular regeneration potential in current MSC-based clinical trials and may change therapeutic strategies away from pure, un-modulated cell delivery concepts.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
05 Vetsuisse Faculty > Institute of Laboratory Animal Science
04 Faculty of Medicine > Center for Medical Research
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiovascular Surgery
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:19 Dec 2011 12:00
Last Modified:05 Apr 2016 15:08
Publisher:Mary Ann Liebert
ISSN:1937-3341
Additional Information:This is a copy of an article published in the Tissue Engineering Part A © 2011 Mary Ann Liebert, Inc.; Tissue Engineering Part A is available online at: http://www.liebertonline.com.
Publisher DOI:10.1089/ten.TEA.2011.0281
PubMed ID:21988679
Permanent URL: http://doi.org/10.5167/uzh-51718

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