Bone marrow cell–induced protection of the human myocardium: Characterization and mechanism of action

Objectives

The mechanism of the putative beneficial effect of myocardial transplantation of bone marrow cells remains unclear. We studied the protective properties of bone marrow cells on the human myocardium and investigated the underlying mechanism.

Methods

Bone marrow cells and the right atrial appendage were obtained from patients undergoing elective cardiac surgery. Myocardial slices were subjected to 90 minutes of simulated ischemia/120 minutes of reoxygenation at 37°C following various protocols. Tissue injury was assessed by creatine kinase released into the media during the reoxygenation period, and myocardial necrosis and apoptosis were determined by propidium iodide and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (percent of aerobic control).

Results

Autologous unfractionated bone marrow cells significantly reduced myocardial injury. Maximal protection was obtained with 5 × 10⁶ autologous cells (∼1.5 × 10⁵ cells/mg wet myocardium) that caused a reduction in creatine kinase release and cell death by necrosis and apoptosis of 70% to 80%. Allogenic bone marrow cells were as protective as the autologous cells and their effect was unaffected by prior frozen storage or culturing. Similar myocardial protection was also attained when bone marrow cells were present only before or during ischemia, or during reoxygenation, a benefit that was comparable with that of ischemic preconditioning. Conditioned media by the bone marrow cells was sufficient to induce protection, which was abolished by the selective insulin-like growth factor-1 receptor blocker PQ401.

Conclusions

Bone marrow cells possess potent myocardial protective properties that are triggered by a secreted factor or factors and mediated by insulin-like growth factor-1 receptor. These results have important clinical implications for the therapeutic use of bone marrow cells in ischemic heart disease and for the design of future clinical studies.

CTSNet classification: 17, 29, 31

Abbreviations and Acronyms: BMC, bone marrow cell, CK, creatine kinase, DAPI, 4′6-diamidino-2-phenylindole, ELISA, enzyme-linked immunosorbent assay, IGF, insulin-like growth factor, IGF-1R, insulin-like growth factor-1 receptor, IP, ischemic preconditioning, I/R, ischemia/reoxygenation, KHH, Krebs/Henseleit/Hepes