Pigment Epithelium-Derived Factor (PEDF) is a Determinant of Stem Cell Fate: Lessons from an Ultra-Rare Disease

Abstract

PEDF is a secreted glycoprotein that is widely expressed by multiple organs. Numerous functional contributions have been attributed to PEDF with antiangiogenic, antitumor, anti-inflammatory, and neurotrophic properties among the most prominent. The discovery that null mutations in the PEDF gene results in Osteogenesis Imperfecta Type VI, a rare autosomal recessive bone disease characterized by multiple fractures, highlights a critical developmental function for this protein. This ultra-rare orphan disease has provided biological insights into previous studies that noted PEDF's effects on various stem cell populations. In addition to bone development, PEDF modulates resident stem cell populations in the brain, muscle, and eye. Functional effects on human embryonic stem cells have also been demonstrated. An overview of recent advances in our understanding by which PEDF regulates stem cells and their potential clinical applications will be evaluated in this review.

Keywords: Wnt signaling; osteogenesis imperfecta; pigment epithelium-derived factor; stem cells.

Figure 1

Schematic diagram of PEDF, its associated peptide regions, and functional effects related to stem cell biology. The N-terminus contains the well-known anti-angiogenesis effects. This region has also been implicated in inhibiting the Wnt receptor, LRP6, in differentiated cells. The 44-mer and a 20-mer within this region have been implicated in neuronal differentiation and muscle progenitor proliferation. The full-length PEDF protein has been shown to induce mesenchymal stem cells (MSC) to the osteoblast lineage and affect pluripotency of embryonic stem cells (ESC) and apoptosis of inducible pluripotent stem cells.

Figure 2

Pigment epithelium-derived factor (PEDF) regulates the proliferation and differentiation of multiple tissue-specific stem cells. PEDF targets proliferating but not resting endothelial cells. PEDF directs mesenchymal stem cells to the osteoblast lineage, while inhibiting adipogenesis. PEDF promotes neurogenesis in neuronal stem cells but causes neuronal differentiation of more committed precursors. PEDF also causes proliferation of muscle progenitors and limbal epithelial cells that are important for corneal regeneration.