title: 3D microtissue formation of undifferentiated bone marrow mesenchymal stem cells leads to elevated apoptosis.
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, unmodulated cell delivery concepts.
authors: Swiss Center for Regenerative Medicine, University of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. jens.kelm@insphero.com
authors: Jens M
authors: JM
authors: Kelm
authors: Martin
authors: M
authors: Breitbach
authors: Gregor
authors: G
authors: Fischer
authors: Bernhard
authors: B
authors: Odermatt
authors: Irina
authors: I
authors: Agarkova
authors: Bernd K
authors: BK
authors: Fleischmann
authors: Simon P
authors: SP
authors: Hoerstrup
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017208:Rats, Wistar; D023822:Tissue Engineering / Q000379:methods