Donor Myocardial Infarction Impairs the Therapeutic Potential of Bone Marrow Cells by an Interleukin-1–Mediated Inflammatory Response

Inflammation after myocardial infarction may explain failure of bone marrow cells to improve cardiac function in infarcted recipient hearts. Getting to the Heart of Bone Marrow Therapy If arteries are the highways of the body, arterial blockage is like a jackknifed tractor-trailer: It blocks the flow of traffic and prevents passage. However, whereas a traffic accident may merely delay your commute, arterial blockage can result in the death of nutrient- and oxygen-starved cells that are no longer fed by the blood, such as happens with a myocardial infarction (MI). In rodent models, cells from the bone marrow can substantially improve cardiac function after MI, but attempts to translate these studies into humans have met with limited success. Now, Wang et al. show that this failure in humans may result from inflammation caused by the MI itself and that blocking inflammation with an inhibitor of the cytokine IL-1 restored the healing power of the bone marrow cells. The difference in outcomes observed in the two systems stemmed from the purity of the mouse system. Because genetically identical mice are readily available, healthy littermates supply more than enough donor bone marrow cells to successfully repair damaged heart tissue. Humans, however, are not quite so uniform. Donor cells had to come from the patients themselves in order to prevent rejection or graft-versus-host disease. Wang et al. hypothesized that bone marrow cells from MI patients would be different from those of healthy donors. To better mimic the human situation, the authors used donor bone marrow cells from mice that suffered MI and found that these cells were also hindered in their ability to repair cardiac function after MI. However, anti-inflammatory treatment of the donor, including inhibition IL-1, restored the ability of these cells to fix cardiac function. This reverse-translation study, which took a clinical observation and attempted to explain it in a rodent model, has not only provided insight into the local environment after MI; it also suggests a new option for successfully treating MI in the clinic. Preventing or reversing the proinflammatory change in the bone marrow cells may help them to cause a change of heart. Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.