PEDF and VEGF-A Output from Human Retinal Pigment Epithelial Cells Grown on Novel Microcarriers

Abstract

Human retinal pigment epithelial (hRPE) cells have been tested as a cell-based therapy for Parkinson's disease but will require additional study before further clinical trials can be planned. We now show that the long-term survival and neurotrophic potential of hRPE cells can be enhanced by the use of FDA-approved plastic-based microcarriers compared to a gelatin-based microcarrier as used in failed clinical trials. The hRPE cells grown on these plastic-based microcarriers display several important characteristics of hRPE found in vivo: (1) characteristic morphological features, (2) accumulation of melanin pigment, and (3) high levels of production of the neurotrophic factors pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A). Growth of hRPE cells on plastic-based microcarriers led to sustained levels (>1 ng/ml) of PEDF and VEGF-A in conditioned media for two months. We also show that the expression of VEGF-A and PEDF is reciprocally regulated by activation of the GPR143 pathway. GPR143 is activated by L-DOPA (1 μM) which decreased VEGF-A secretion as opposed to the previously reported increase in PEDF secretion. The hRPE microcarriers are therefore novel candidate delivery systems for achieving long-term delivery of the neuroprotective factors PEDF and VEGF-A, which could have a value in neurodegenerative conditions such as Parkinson's disease.

Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation

“…One key difference in any double-blind, sham-controlled preclinical or clinical study is that animals do not develop placebo effects as compared with patients undergoing the same trial. Nonetheless, the efficacy of this therapy may be improved by increasing the numbers of fetal-derived hRPE cells or enhancing their survival after implantation with the use of novel microcarriers (32).…”

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

“…Once established, the RPE aids in homeostasis, function, and survival of photoreceptor cells. The RPE participates in metabolic transport between the subretinal space and blood, production of cytokines and immunosuppressive factors, and secretion of growth factors, such as brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) (Dornonville de la Cour, 1993; Falk et al, 2012; Gao and Hollyfield, 1992; Ishida et al, 2003, 1997; Kliffen et al, 1997; Kvanta, 1995; Lopez et al, 1996; Park and Hollenberg, 1989; Schweigerer et al, 1987; Steinberg, 1985; Sternfeld et al, 1989; Streilen et al, 2002; Sugita et al, 2009, 2006; Tombran-Tink et al, 1995; Zamiri et al, 2006). …”

TFAP2A Regulates Nasopharyngeal Carcinoma Growth and Survival by Targeting HIF-1α Signaling Pathway

“…Under hypoxic conditions, HIF-1a forms a heterodimer with HIF-1b, and binds to the hypoxia-responsive elements of the promoters to activate downstream hypoxia-responsive genes, including VEGF, to increase angiogenesis and tumor metastasis or to promote cancer cell proliferation and migration (35)(36)(37). VEGF has a crucial role in pathologic angiogenesis associated with tumors, intraocular neovascular disorders, and other conditions (36,37). The potent angiogenic inhibitor pigment epithelium-derived factor (PEDF) counterbalances the effect of VEGF (38).…”