Leukemia Inhibitory Factor Influences the Fate Choice of Mesenchymal Progenitor Cells

Abstract

Osteoblasts and adipocytes derive from a common mesenchymal precursor, and in at least some circumstances, differentiation along these two lineages is inversely related. For example, we have recently observed that concomitant with inhibition of osteoblast differentiation and bone nodule formation, leukemia inhibitory factor (LIF) induces genes regulating lipid metabolism in fetal rat calvaria (RC) cell cultures. In this study, we further investigated the adipogenic capacity of LIF-treated RC cells. Quantitative analyses revealed that LIF increased the adipocyte differentiation induced by the peroxisome proliferator-activated receptor ␥ agonist BRL49653 (BRL) in RC cell populations. Gene expression profiling of individual RC cell colonies in untreated cells or cells treated with LIF, BRL, or combined LIF-BRL suggested that some adipocytes arose from bipotential or other primitive precursors, including osteoprogenitors, since many colonies co-expressed osteoblast and adipocyte differentiation markers, whereas some arose from other cell pools, most likely committed preadipocytes present in the population. These analyses further suggested that LIF and BRL do not act at the same stages of the mesenchymal hierarchy, but rather that LIF modifies differentiation of precursor cells, whereas BRL acts later to favor adipocyte differentiation. Taken together, our data suggest that LIF increased adipocyte differentiation at least in part by altering the fate of osteoblastic cells and their precursors. STEM CELLS 2007;25:305-312

Aging alters bone-fat reciprocity by shifting in vivo mesenchymal precursor cell fate towards an adipogenic lineage

“…Increases in MPCs committed towards the adipocyte lineage and decreases in those committed towards the osteoblast lineage with age could possibly explain their reciprocal representation in aging bone [13]. This hypothesis is supported by in vitro experiments on bone marrow-derived MPCs showing that factors which induce adipocyte differentiation inhibit osteoblast differentiation [14, 15], while those that induce osteoblast differentiation inhibit adipogenesis [16, 17]. Several factors and signaling pathways have been implicated in the control of MPC differentiation into osteoblastic and adipocytic cells, including TAZ (transcriptional coactivator with PDZ-binding motif) [18], PPARg2 [19], ΔFosB [20], canonical Wnt-β-catenin and non-canonical Wnt signaling pathways [21].…”

Deletion of the nuclear localization sequence and C-terminus of parathyroid hormone–related protein decreases osteogenesis and chondrogenesis but increases adipogenesis and myogenesis in murine bone marrow stromal cells

“…We also found increased Lif expression in Pthrp Δ/Δ BMSCs, consistent with its pro-adipogenic, pro-myogenic, and anti-osteogenic effects. 33,34 Klf4 was also increased in Pthrp Δ/Δ BMSCs, which increases adipogenesis and myogenesis. 35,36 We found increased Pth1r and Lrp6 expression in Pthrp Δ/Δ BMSCs.…”

Hematopoietic Stem Cells Are Coordinated by the Molecular Cues of the Endosteal Niche

“…Another cytokine expressed by osteoblasts, which has shown to be involved in hematopoiesis, is leukemia inhibitory factor (LIF) [ 27 ]. LIF is widely expressed throughout the body and it is involved in controlling self-renewal and cell fate of several precursor cell types, like MSCs, spiral-ganglion neuron precursors, and embryonic germ cells [40][41][42]. LIF has shown to play a regulatory role during hematopoiesis as well.…”