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Bone marrow cells regenerate infarcted myocardium

Abstract

Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time1. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation2,3,4,5; these events promote structural and functional repair6,7,8. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein9 by fluorescence-activated cell sorting on the basis of c-kit expression10. Shortly after coronary ligation, Lin- c-kit POS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9?days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

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Figure 1: Bone marrow cells and myocardial regeneration.
Figure 2: Myocardial infarct injected with Lin-c-kit POS cells; myocardium is regenerating from endocardium (EN) to epicardium (EP).
Figure 3: Regenerating myocardium in myocardial infarct injected with Lin- c-kit POS cells.
Figure 4: Myocardial repair and connexin 43.
Figure 5: Myocardial infarcts injected with Lin-c-kit POS cells: regenerating myocytes.
Figure 6: Postulated mechanism of myocardial regeneration and its effect on ventricular function.

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Acknowledgements

We thank Dr S. Izumo for providing us with the Csx2.5 antibody. This work was supported by grants from the NIH. S.C. is supported by a fellowship from the Mario Negri Institute of Pharmacologic Research, Milan, Italy.

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Correspondence to Piero Anversa.

Supplementary information

FACS of mouse bone marrow: Lin- bone marrow cells from EGFP transgenic mice sorted by FACS based on c-kit expression. The fraction of c-kit POS cells (upper gate) was 6.4%: c-kit NEG cells are shown in the lower gate. c-kit POS cells were 1-2 logs brighter than c-kit NEG cells.

EGFP Localization: MI injected with Lin- c-kitPOS cells. Border zone; viable myocardium (VM) and new band (NB) of myocardium separated by an area of infarcted non-repairing tissue (arrows). A: EGFP (green); B: Cardiac myosin (red); C: Combination of EGFP and myosin (red- green); PI-stained nuclei (blue). A-C, X280.

Y Chromosome Localization:A-C: MI injected with Lin- c-kitPOS cells; regenerating myocardium (arrowheads). A: Cardiac myosin (red); B: Y chromosome (green); C: Combination of Y chromosome (light blue) and PI-labeled nuclei (dark blue). Lack of Y chromosome in infarcted tissue (IT) in subendocardium and spared myocytes (SM) in subepicardium. A-C, X400.

EGFP Localization in the Myocardium: Regenerating myocardium in MI injected with Lin- c- kitPOS cells. A,D: EGFP (green); B: Cardiac myosin (red); E: _-smooth muscle actin in arterioles (red); C: Combination of EGFP and myosin staining (yellow); F: Combination of EGFP and _- smooth muscle actin (yellow-red); C,F: PI-stained nuclei (blue). A-F, X650.

Expression of GATA-4: GATA-4 in cardiac myosin positive cells. A: PI-stained nuclei (blue); B: GATA-4 labeling (green); C: Cardiac myosin (red); combination of GATA-4 with PI (bright fluorescence in nuclei). A-C, X650.

BrdU and Ki67 Labeling: A-F: Regenerating myocardium in MI injected with Lin- c-kitPOS cells. A-C: BrdU; D-F: Ki67. A,D: PI-labeled nuclei (blue); B,E: BrdU- and Ki67-labeled nuclei (green); C: _-sarcomeric actin (red); F: _-smooth muscle actin (red). Bright fluorescence: combination of PI with BrdU (C) or Ki67 (F). A-C, X900; D-F, X500.

Lin- c-kitPOS Cell in the Infarcted Myocardium. MI injected with Lin- c-kitPOS cells. Undifferentiated small cell; A: c-kit labeling on the cell surface (green); B: EGFP (red); C: c-kit and EGFP (yellow-green-red). PI-labeled nuclei (blue). EGFP negative cells (nuclei) outside the regenerating myocardium. A-C, X1,500.

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Orlic, D., Kajstura, J., Chimenti, S. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001). https://doi.org/10.1038/35070587

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