Determination of mesenchymal stem cell fate by pigment epithelium‐derived factor (PEDF) results in increased adiposity and reduced bone mineral content

Abstract

Pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, has been linked to distinct diseases involving adipose or bone tissue, the metabolic syndrome, and osteogenesis imperfecta (OI) type VI. Since mesenchymal stem cell (MSC) differentiation into adipocytes vs. osteoblasts can be regulated by specific factors, PEDF-directed dependency of murine and human MSCs was assessed. PEDF inhibited adipogenesis and promoted osteoblast differentiation of murine MSCs, osteoblast precursors, and human MSCs. Blockade of adipogenesis by PEDF suppressed peroxisome proliferator-activated receptor-γ (PPARγ), adiponectin, and other adipocyte markers by nearly 90% compared with control-treated cells (P<0.001). Differentiation to osteoblasts by PEDF resulted in a common pathway that involved PPARγ suppression (P<0.01). Canonical Wnt-β-catenin signaling results in a MSC differentiation pattern analogous to that seen with PEDF. Thus, adding PEDF enhanced Wnt-β-catenin signal transduction in human MSCs, demonstrating a novel Wnt agonist function. In PEDF knockout (KO) mice, total body adiposity was increased by >50% compared with controls, illustrating its systemic role as a negative regulator of adipogenesis. Bones from KO mice demonstrated a reduction in mineral content recapitulating the OI type VI phenotype. These results demonstrate that the human diseases associated with PEDF reflect its ability to modulate MSC differentiation.

PEDF-induced alteration of metabolism leading to insulin resistance

“…This finding contrasted an earlier study that showed that PEDF is synthesised by adipose tissue and is downregulated during differentiation to mature adipocytes (Kratchmarova et al, 2002). PEDF can block mesenchymal stem cell (MSC) differentiation to adipocytes in order to facilitate differentiation to osteoblasts (Gattu et al, 2013). In PEDF −/− mice, total body adiposity was increased by >50% compared with controls, illustrating its systemic role as a negative regulator of adipogenesis.…”

Pigment epithelium derived factor upregulates expression of vascular endothelial growth factor by human mesenchymal stem cells: Possible role in PEDF regulated matrix mineralization

“…Mechanisms by which PEDF regulates bone mineralization remain undefined. We and others showed that PEDF increased MSCs-osteoblastic mineralization; in addition, we showed that PEDF enhanced expression of genes that encode proteins which promote matrix mineralization [11,12]. In this report, we examined whether VEGF which plays important role in bone development is also regulated by PEDF.…”

“…The major bone defect in these patients is presence of excessive osteoid build up that fails to mineralize [7–10]. We and others have shown that PEDF promotes mesenchymal stem cell differentiation and increases osteoblast mineralization [11,12]. In addition, we reported that PEDF reduced expression of sclerostin by osteocytes [13].…”

Adipocyte transdifferentiation and its molecular targets

“…The lineage commitment of mesenchymal stem cells is controlled by different groups of protein such as bone morphogenic protein family (BMP), hedgehog protein family, nuclear hormone super family, wingless protein family, etc. (Busser et al, 2013;Gattu et al, 2013). The role of each transcription factor is explained in detail in the following sections.…”