Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions

Cardiogenesis is a multistep process regulated by a hierarchy of factors de fining each developmental stage of the heart. One of these factors, leukemi a inhibitory factor (LIF), a member of the interleukin-g family of cytokine s, is expressed in embryonic and neonatal cardiomyocytes and induces cardio myocyte hypertrophy. Many aspects of embryogenesis are faithfully recapitul ated during in vitro differentiation of embryonic stem cells in embryoid bo dies. We exploited this model to study effects of growth factors on commitm ent and differentiation of cardiomyocytes and on maintenance of their pheno type. We identified LIF as a factor affecting commitment and differentiatio n of cardiomyocytes in an opposite manner. Diffusible LIF inhibited mesoder m formation and hampered commitment of cardiomyocytes. Lack of both the dif fusible and matrix-bound isoforms of LIF in lifr-/- embryoid bodies did not interfere with commitment, but it severely suppressed early differentiatio n of cardiomyocytes. Onset of differentiation was rescued by very low conce ntrations of diffusible LIF; however, consecutive differentiation was atten uated in a concentration-dependent manner by diffusible LIF both in wild-ty pe and lif-/- cardiomyocytes. Differentiation of cardiomyocytes was severel y hampered but not completely blocked in lif-/- embryoid bodies, suggesting additional, LIF-receptor ligand independent pathways for commitment and di fferentiation of cardiomyocytes. At the fully differentiated state, both pa racrine and autocrine LIF promoted proliferation and increased longevity of cardiomyocytes. These findings suggest that both paracrine and autocrine a nd both diffusible and matrix-bound isoforms of LIF contribute to the modul ation of cardiogenesis in a subtle, opposite, and developmental stage-depen dent manner and control proliferation and maintenance of the differentiated state of cardiomyocytes.