Researchers have identified hematopoietic stem and progenitor cells (HSPCs) that are liberated from bone marrow niches by a myocardial infarction (MI). These progenitor cells migrate from the bone marrow and seed the spleen. From there they provide a sustained boost in monocyte production that can contribute to artherogenesis. These cells and the process behind their release represent a novel therapeutic opportunity for survivors of MI.
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“We have a good explanation why reinfarction is frequent: MI accelerates atherosclerosis,” explains Matthias Nahrendorf, MD, PhD. Dr. Nahrendorf is assistant professor at Harvard Medical School, Boston, and one of the corresponding authors of a related study published in Nature.1
MI and stroke are triggered by the destabilization and rupture of lipid-rich plaques in the arterial wall. Patients who survive acute coronary syndromes go on to have a higher risk for recurrent events. The biological connection between the first event and recurrent events was previously unknown. Dr. Nahrendorf and colleagues demonstrate that acute MI or stroke increases arthrosclerosis as well as inflammation in distal atherosclerotic plaques.
The study utilized Apoe-/- mice that develop spontaneous atherosclerotic lesions. The researchers imaged protease activity in these mice and used the activity as a marker of plaque lesion vulnerability. They found that after MI or stroke, Apoe-/- mice developed larger atherosclerotic lesions that persisted over many weeks and contained a large number of monocytes. They then searched for the source of the surplus monocytes in the plaques.
When they measured monocyte progenitor content in mice after MI, they found an increase in the spleen. When mice were splenectomized at the time of MI, there was no acceleration in atherosclerosis.
A Puzzling Finding
The researchers were puzzled, however, because granulocyte macrophage progenitors and macrophage dendritic cell progenitors have only a limited capacity for self-renewal. This limitation was not consistent with the large numbers of monocytes that were exiting the spleen and entering the plaques. Upon further investigation, they discovered that the monocyte progenitor cells did not originate in the spleen, but rather resulted from a burst in inflammatory cells in the bone marrow.
As Dr. Nahrendorf explains, “Atherosclerosis is an inflammatory disease starting in the bone marrow. This, in addition to the spleen, is where macrophages are made.”
It appears that the sympathetic nervous system liberates the hematopoietic cells from their niches by signaling through the β3-adrenoceptor. Indeed, treatment with a β3-adrenoceptor blocker in wild-type mice reduced splenic accumulation of progenitors after MI. Treatment of Apoe-/- mice with a β3-blocker lowered protease activity, myeloid cell count, and mRNA levels of inflammatory cytokines in the plaque.
When fluorescent membrane dye-labeled HSPCs were adoptively transferred into a host, they settled in the bone marrow before the MI, and 52% migrated from the bone marrow post MI. The process appeared to be stem cell factor (SCF)–dependent because neutralization of SCF inhibited proliferation of host HSPCs as well as splenic retention of adoptively transferred HSPCs.
Although most scientists agree that atherosclerosis can be described as chronic inflammatory in nature, there is not yet an antiinflammatory therapy that is specific for atherosclerosis. “In my eyes, this opens up a new line of research and new therapeutic opportunities. In any inflammatory disease, including rheumatoid arthritis and atherosclerosis, we have to take the production of immune cells into account,” says Dr. Nahrendorf.
Dr. Pullen is a medical writer based in the Chicago area.
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