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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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References

  1. Pfeffer, M. A. & Braunwald, E. Ventricular remodeling after myocardial infarction. Circulation81, 1161–1172 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science279, 1528–1530 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Jackson, K. A., Mi, T. & Goodell, M. A. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc. Natl Acad. Sci. USA96, 14482–14486 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Eglitis, M. A. & Mezey, E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc. Natl Acad. Sci. USA94, 4080–4085 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Theise, N. D. et al. Liver from bone marrow in humans. Hepatology32, 11–16 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Brazelton, T. A., Rossi, F. M. V., Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science290, 1775–1779 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A. & McKercher, S. R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science290, 1779–1782 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Vogel, G. Stem cells: new excitements, persistent questions. Science290, 1672–1674 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Hadjantonakis, A. K., Gerstenstein, M., Ikawa, M., Okabe, M. & Nagy, A. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech. Dev.76, 79–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Orlic, D., Fischer, R., Nishikawa, S.-I., Nienhuis, A. W. & Bodine, D. M. Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c-kit receptor. Blood82, 762–770 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Li, Q. et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J. Clin. Invest.100, 1991–1999 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Durocher, D., Charron, F., Warren, R., Schwartz, R. J. & Nemer, M. The cardiac transciption factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J.16, 5687–5696 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morin, S., Charron, F., Robitaille, L. & Nemer, M. GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J.19, 2046–2055 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beardsle, M. A., Laing, J. G., Beyer, E. C. & Saffitz, J. E. Rapid turnover of connexin43 in the adult rat heart. Circ. Res.83, 629–635 (1998).

    Article  Google Scholar 

  15. Musil, L. S., Le, A. N., VanSlyke, J. K. & Roberts, L. M. Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J. Biol. Chem.275, 25207–25215 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Scholzen, T. & Gerdes, J. The ki-67 protein: from the known and the unknown. J. Cell. Physiol.182, 311–322 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Kajstura, J. et al. Myocyte cellular hyperplasia and myocyte cellular hypertrophy contribute to chronic ventricular remodeling in coronary artery narrowing-induced cardiomyopathy in rats. Circ. Res.74, 383–400 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Clarke, D. L. Generalized potential of adult neural stem cells. Science288, 1660–1663 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Theise, N. D. et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology31, 235–240 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nature Med.6, 1229–1234 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Kunisada, T. et al. Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development125, 2915–2923 (1998).

    CAS  PubMed  Google Scholar 

  22. Matsui, Y., Zsebo, K. M. & Hogan, B. Embryonic expression of a haematopoietic growth factor encoded by the S1 locus and the ligand for c-kit. Nature347, 667–669 (1990).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Morrison, S. J., Uchida, N. & Weissman, I. L. The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol.11, 35–71 (1994).

    Article  Google Scholar 

  24. Morrison, S. J., Shah, N. M. & Anderson, D. J. Regulatory mechanisms in stem cell biology. Cell88, 287–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Tomita, S. et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation100 (Suppl.), II-247–II-256 (1999).

    Article  CAS  Google Scholar 

  26. Li, B. et al. Insulin-like growth factor-1 attenuates the detrimental impact of non occlusive coronary artery constriction on the heart. Circ. Res.84, 1007–1019 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Leri, A. et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J. Clin. Invest.101, 1326–1342 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kajstura, J. et al. Myocyte proliferation in end-stage cardiac failure in humans. Proc. Natl Acad. Sci. USA95, 8801–8805 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kajstura, J. et al. Telomere shortening is an in vivo marker of myocyte replication and aging. Am. J. Pathol.156, 813–819 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leri, A. et al. Pacing-induced heart failure in dogs enhances the expression of p53 and p53-dependent genes in ventricular myocytes. Circulation97, 194–203 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

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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