Hematopoietic cytokines for cardiac repair: mobilization of bone marrow cells and beyond

Abstract

Hematopoietic cytokines, traditionally known to influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow, include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, stem cell factor, Flt-3 ligand, and erythropoietin among others. Emerging evidence suggests that these cytokines also exert multifarious biological effects on diverse nonhematopoietic organs and tissues. Although the precise mechanisms remain unclear, numerous studies in animal models of myocardial infarction (MI) and heart failure indicate that hematopoietic cytokines confer potent cardiovascular benefits, possibly through mobilization and subsequent homing of bone marrow-derived cells into the infarcted heart with consequent induction of myocardial repair involving multifarious mechanisms. In addition, these cytokines are also known to exert direct cytoprotective effects. However, results from small-scale clinical trials of G-CSF therapy as a single agent after acute MI have been discordant and largely disappointing. It is likely that cardiac repair following cytokine therapy depends on a number of known and unknown variables, and further experimental and clinical studies are certainly warranted to accurately determine the true therapeutic potential of such therapy. In this review, we discuss the biological features of several key hematopoietic cytokines and present the basic and clinical evidence pertaining to cardiac repair with hematopoietic cytokine therapy.

Fig. 1

Schematic representation of hematopoiesis in which pluripotent stem and progenitor cells in the bone marrow divide and differentiate, passing through intermediate steps to form red blood cells, platelets, and white blood cells. The specific roles of hematopoietic cytokines known to stimulate transitions are indicated

Fig. 2

Schematic representation of intracellular signaling pathways activated by G-CSF via the activation of G-CSF receptor complex. Activation of JAK/STAT, MAPK, and PI3-K/Akt pathways leads to inhibition of apoptosis, cell survival, and differentiation

Fig. 3

Potential mechanisms underlying the cardioprotective actions of G-CSF. G-CSF stimulates mobilization of BMCs, which can home to the heart to initiate myocardial repair via several mechanisms: a differentiation into cells of cardiac lineages; b activation of antiapoptotic signaling; c promote angiogenesis and reendothelialization; d paracrine effects on resident progenitors and myocytes leading to cellular proliferation; e and favorable paracrine effects on the extracellular matrix. Apart from these BMC-mediated effects, G-CSF can also exert direct cytoprotective and angiogenic effects on the infarcted myocardium