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Abstract
BackgroundDespite positive reports on the efficacy of stem cell therapy for the treatment of cardiovascular disease, the nature of stem cell homing to ischemic tissues remains elusive.ResultsWe used a mouse model of peripheral tissue ischemia to study the survival and homing capacity of dual reporter gene (eGFP/Luciferase) expressing bone marrow-derived stromal cells (BMSC). Cell homing and survival were studied in the presence and absence of ciclosporin A (CsA) immunosuppression using bioluminescence imaging (BLI) together with confocal endomicroscopy. Different injection strategies were applied: central venous (CV), intra-arterial (IA) and intramuscular (IM). BLI and confocal endomicroscopy evidenced complete rejection of the IM injected allogeneic BMSC transplant within 5 to 10 days. Immunosuppression with CsA could only marginally prolong graft survival. IM injected BMSC did not migrate to the site of the arterial ligation. CV injection of BMSC resulted in massive pulmonary infarction, leading to respiratory failure and death. Intrapulmonary cell trapping was evidenced by confocal endomicroscopy, BLI and fluorescence microscopy. IA injection of BMSC proved to be a feasible and safe strategy to bypass the lung circulation. During the follow-up period, neither BLI nor confocal endomicroscopy revealed any convincing ischemia-directed homing of BMSC.ConclusionsBLI and confocal endomicroscopy are complementary imaging techniques for studying the in vivo biology of dual reporter gene-expressing BMSC. Allogeneic BMSC survival is limited in an immunocompetent host and cannot be preserved by CsA immunosuppression alone. We did not find substantial evidence for ischemia-directed BMSC homing and caution against CV injection of BMSC, which can lead to massive pulmonary infarction.
Highlights
Despite positive reports on the efficacy of stem cell therapy for the treatment of cardiovascular disease, the nature of stem cell homing to ischemic tissues remains elusive
Survival and migration characteristics of locally injected bone marrow-derived stromal cells (BMSC) To study the in vivo survival and migration characteristics of IM injected BMSC, cells were transplanted into the calf muscles 24 h after induction of hindlimb ischemia
EGFP fluorescence intensity and Luciferase activity were checked by confocal endomicroscopy and bioluminescence imaging methods, respectively (Figure 1)
Summary
Despite positive reports on the efficacy of stem cell therapy for the treatment of cardiovascular disease, the nature of stem cell homing to ischemic tissues remains elusive. Mesenchymal stem cell (MSC) therapy is currently being explored in almost any clinical field involving tissue restoration or modulation of immune responses [1]. This widely applicable, simple and straightforward therapy would represent a milestone in modern medicine. Society for Cellular Therapy, in an effort to facilitate data exchange between investigators, came up with a set of minimal criteria to define human MSC These cells should be plastic-adherent when maintained in standard culture conditions, have multilineage differentiation potential into osteoblasts, adipocytes and chondroblasts in vitro and express a specific set of cellular markers. Whole-body imaging techniques using radioactive or magnetic labeling dyes, fluorescent markers or reporter genes, all have disadvantages and probably a combination of different imaging modalities is needed to provide a reliable picture
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