Successful implantation of intravenously administered stem cells correlates with severity of inflammation in murine myocarditis

Abstract

The present study was designed to determine whether cardiac inflammation is important for the successful homing of stem cells to the heart after intravenous injection in a murine myocarditis model. Male Bagg albino/c mice were infected with encephalomyocarditis virus (EMCV) to produce myocarditis. Subgroups of mice received single injections by tail vein of embryonic stem cells (ESCs) transfected with green fluorescent protein (GFP) as a marker at days 3, 14, or 60 after infection; other subgroups without stem cell injections were killed at each of these time points to assess the degree of inflammation present. The surviving mice were killed at day 90 after virus infection and hemodynamics, gross pathology, histology, and inflammatory cytokine production in the hearts were measured. Our results indicate that myocardial inflammation was most severe and cytokine production highest at day 14 after EMCV inoculation, and in particular, was strongly positive for interleukin 6. Mice receiving intravenous ESC injections on day 14 after EMCV inoculation showed the largest number of GFP-positive cells at the time of death and the greatest functional improvement compared to uninfected controls without inflammation. We conclude that factors released from myocardium during inflammation are important for enhancing the homing, migration, and implantation of systemically infused stem cells.

The Stem Cell Movement

“…94,115 Malek et al addressed the issue of whether cardiac inflammation plays an important role in successful homing of ES cells to the heart after intravenous delivery in a murine myocarditis model. 116 Maximal engraftment of ES cells occurred at a time of peak inflammatory cytokine production, most notably IL-6, supporting the notion that factors released from the myocardium during an inflammatory response, as occurs in MI, are important for enhancing the homing, migration, and implantation of systemically infused stem cells. Extrapolating to humans, these conclusions raise the possibility that cell transplantation may be a less effective therapy for patients who do not manifest a significant degree of cardiac inflammation, notably patients with end-stage cardiomyopathy.…”

Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells

“…Previous studies have shown the importance of inflammation to the successful homing of systematically infused stem cells (HSC) to cardiac tissue, 15 thus reinforcing the notion of inflammation and chemokine production in migration of MSC. In addition to the secreted chemotactic molecules secreted by the tumor and its surrounding stroma, the tumor cells themselves retain a chemotactic disparity amongst its cellular components.…”

Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study

“…Cell necrosis after an injury such as myocardial infarction may cause the release of signals into the circulatory system, and these could induce the homing of stem cells to the myocardium. The intense inflammatory reaction after myocardial infarction may cause a local accumulation of mast cells, which might also contribute to the homing of MSCs [9,13]. The injured tissue may express receptors or ligands that facilitate the trafficking and adhesion of stem cells to the site of injury, where differentiation is initiated, resulting in the generation of cells of the appropriate lineage [1,5,7].…”