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.

Pigmentation Is Associated with Stemness Hierarchy of Progenitor Cells Within Cultured Limbal Epithelial Cells

“…PEDF was first identified as a 50 kDa secreted protein in conditioned medium from cultured fetal human retinal pigment epithelium (RPE) cells , and was recognized as a potent inhibitor of vascular endothelial growth factor (VEGF) . Recently, PEDF was proposed to regulate the proliferation and differentiation of human embryonic stem cells as well as multiple tissue‐specific stem cells , and was also found in developing and mature human cornea . With regard to hLESCs, it has been reported that the PEDF has the capacity to promote self‐renewal and that such effect may be associated with the p63 expression .…”

Identification of proteins associated with paclitaxel resistance of epithelial ovarian cancer using iTRAQ‑based proteomics

“…PEDF is a secreted factor with multiple biological functions. It was initially considered to be a neurotrophic factor, but its recognized functions later expanded to include a stem cell niche factor, an inhibitor of cancer cell growth and, notably, the most potent natural antiangiogenic factor ( 34 – 36 ). A number of animal models have demonstrated the therapeutic value of PEDF in the treatment of blinding diseases and multiple types of cancer.…”

Pigment Epithelium-Derived Factor and its Phosphomimetic Mutant Induce JNK-Dependent Apoptosis and P38-Mediated Migration Arrest

“…PEDF has been originally identified in the retina, however, it has now become evident that it is expressed throughout the human body and is constantly present in the systemic circulation [4,5]. Studies in the past years have implicated PEDF in the pathophysiology of a wide range of angiogenesis-associated disorders, including diabetic complications [6,7], macular degeneration [8,9], Osteogenesis Imperfecta Type VI [10,11], and the growth of many types of solid tumors [12][13][14][15][16]. Some of these roles may be mediated by the effect of PEDF on stem cells as was shown in the brain, muscle, and eye [11].…”

“…Studies in the past years have implicated PEDF in the pathophysiology of a wide range of angiogenesis-associated disorders, including diabetic complications [6,7], macular degeneration [8,9], Osteogenesis Imperfecta Type VI [10,11], and the growth of many types of solid tumors [12][13][14][15][16]. Some of these roles may be mediated by the effect of PEDF on stem cells as was shown in the brain, muscle, and eye [11]. Furthermore, the natural antiangiogenic activity of PEDF, which is far greater than that of any other known endogenously produced factor [2,17], has turned it into a highly potent therapeutic agent for the inhibition of pathological neovascularization and, therefore, a promising tumor suppressor [18].…”