Discrepant Results of Experimental Human Mesenchymal Stromal Cell Therapy after Myocardial Infarction: Are Animal Models Robust Enough?

BACKGROUND: Human mesenchymal stromal cells (MSCs) have been reported to preserve cardiac function in myocardial infarction (MI) models. Previously, we found a beneficial effect of intramyocardial injection of unstimulated human MSCs (uMSCs) on cardiac function after permanent coronary artery ligation. In the present study we aimed to extend this research by investigating the effect of intramyocardial injection of human MSCs pre-stimulated with the pro-inflammatory cytokine interferon-gamma (iMSCs), since pro-inflammatory priming has shown additional salutary effects in multiple experimental disease models. METHODS: MI was induced in NOD/Scid mice by permanent ligation of the left anterior descending coronary artery. Animals received intramyocardial injection of uMSCs, iMSCs or PBS. Sham-operated animals were used to determine baseline characteristics. Cardiac performance was assessed after 2 and 14 days using 7-Tesla magnetic resonance imaging and pressure-volume loop measurements. Histology and q-PCR were used to confirm MSC engraftment in the heart. RESULTS: Both uMSC and iMSC therapy had no significant beneficial effect on cardiac function or remodelling in contrast to our previous studies. CONCLUSIONS: Animal models for cardiac MSC therapy appear less robust than initially envisioned.

Myocardial infarction models in NOD/Scid mice for cell therapy research: permanent ischemia vs ischemia-reperfusion.

Myocardial infarction animal studies are used to study disease mechanisms and new treatment options. Typically, myocardial infarction (MI) is induced by permanent occlusion of the left anterior descending artery. Since in MI patients coronary blood flow is often restored new experimental models better reflecting clinical practice are needed. Here, permanent ischemia MI (PI group) was compared with transient ischemia (45 min) (IR group) in immunodeficient NOD/Scid mice. Cardiac function, infarct size, wall thickness and total collagen deposition were significantly reduced only in PI mice. Cardiac inflammatory cells and serum cytokine levels were less dynamic in IR animals compared to PI. So although IR better reflects clinical practice, it is secondary to PI for investigating cell therapy, since it induces too little damage to provide a measurable therapeutic window. MI did result in significant changes in the inflammatory state, indicating this immunodeficient mouse strain is valuable to study human cell therapy.

Post-myocardial infarct inflammation and the potential role of cell therapy.

Myocardial infarction triggers reparative inflammatory processes programmed to repair damaged tissue. However, often additional injury to the myocardium occurs through the course of this inflammatory process, which ultimately can lead to heart failure. The potential beneficial effects of cell therapy in treating cardiac ischemic disease, the number one cause of death worldwide, are being studied extensively, both in clinical trials using adult stem cells as well as in fundamental research on cardiac stem cells and regenerative biology. This review summarizes the current knowledge on molecular and cellular processes implicated in post-infarction inflammation and discusses the potential beneficial role cell therapy might play in this process. Due to its immunomodulatory properties, the mesenchymal stromal cell is a candidate to reverse the disease progression of the infarcted heart towards heart failure, and therefore is emphasized in this review.