Myocardial Infarction Activates CCR2+ Hematopoietic Stem and Progenitor Cells

Abstract

SUMMARY Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlate closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. CCR2+ HSPC have fourfold higher proliferation rates than CCR2−CD150+CD48− LSK cells, display a myeloid differentiation bias, and dominate the migratory HSPC population. We further demonstrate the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury, and identify potential therapeutic targets to modulate leukocyte output after MI.

Monocytes and macrophages in cardiac injury and repair

“…These myeloid cells are deployed to the cardiac wound and promote infarct healing. In patients with acute MI, a similar BM activation was observed after ischemia (26).…”

“…Granulocyte/macrophage precursors (GMPs) originate from hematopoietic stem and progenitor cells and mature into macrophage (monocyte)/dendritic cell precursors (MDPs), which give rise to Ly6C high monocytes through common monocyte progenitors (cMoPs) (25). The role of the BM in the inflammatory response that follows MI was recently investigated (26). BM hematopoietic stem cells (HSC) are activated after MI and give rise to a subset of CCR2+ HSCs that proliferate vigorously in response to ischemia increasing the production of myeloid cells (monocytes, macrophages, neutrophils).…”

Bone marrow drives central nervous system regeneration after radiation injury

“…We were particularly interested in defining whether hematopoietic cells were directly involved in repair because work by others had shown myeloid cell localization and response to injury in retina (23), brain (24,25), spinal cord (26), and infarcted myocardium (27). In particular, it has been shown that damaged myocardium induces the release of CCR2 + myeloid cells from bone marrow, which in turn is associated with improved cardiac regeneration (28). We therefore asked whether hematopoietic cells could alter the negative impact of irradiation on the central nervous system, on both a structural and functional level.…”

Targeted therapeutics in inflammatory atherosclerosis

“…Although bone marrow is the major source of blood monocytes, extramedullar hematopoiesis (i.e. outside the bone marrow), especially in the spleen, is also driven by inflammation [170,171] (Figure 3). After fetal development, splenic hematopoiesis remains dormant, and the spleen acts as a reservoir seeded with HSCs mobilized from the bone marrow.…”

“…After fetal development, splenic hematopoiesis remains dormant, and the spleen acts as a reservoir seeded with HSCs mobilized from the bone marrow. However, these spleen-resident HSCs are highly responsive, and they regain their proliferative capacity upon exposure to hormonal and inflammatory cues [170,172,173]. For example, inflammatory conditions, such as atherosclerosistriggered ischemic events, can activate splenic hematopoiesis and result in overproduction and deployment of splenic inflammatory monocytes into the circulation [172].…”