Cyclic 3',5'-Adenosine Monophosphate Modulates Retinal Pigment Epithelial Cell Migration In Vitro

Hackett, Sean F.; Friedman, Zvi; Campochiaro, Peter A.

doi:10.1001/archopht.1986.01050230126047

Cited by 12 publications

(5 citation statements)

References 19 publications

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“…In the first instance, we have shown that manipulating cAMP levels significantly impacts the reattainment of the RPE phenotype in a time-and density-dependent manner. Published literature suggested that cAMP exerts direct effects on RPE phenotypes, such as pigmentation and phagocytosis, while inhibiting RPE proliferation [25,26]. We show that elevating cAMP levels in dissociated RPE cells through FSK treatment or use of the cell-permeant cAMP analog dbcAMP increases acquisition of RPE phenotype through increasing proliferation.…”

Section: Discussionmentioning

confidence: 75%

“…Next, we wanted to understand the pathways underlying RPE epithelialization and identify their putative modulators. Given the literature suggesting effects of cAMP signaling on RPE characteristics [21][22][23][24][25], we selected forskolin (FSK) as a tool to increase intracellular cAMP levels. We found that treatment with 10 mM FSK led to a consistent increase in pigmentation and epithelial characteristics across a range of seeding densities ( Fig.…”

Section: Increasing Camp Levels Promotes Acquisition Of Rpe Identity mentioning

confidence: 99%

“…Approaches to increase cAMP (e.g., with the use of vasointestinal peptide, a hormone that raises intracellular cAMP) have been utilized in directing differentiation of embryonic stem cells toward the RPE lineage [9]. Similarly, review of the literature suggests that cAMP signaling controls migratory and fibrotic responses similar to those seen in PVR [25–27]. Therefore, we sought to determine whether cAMP treatment impacted gain of RPE identity during in vitro dissociation and culture of hESC‐derived RPE.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

Choudhary

Gutteridge

Impey

et al. 2016

Stem Cells Translational Medicine

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Retinal pigment epithelium (RPE) cell integrity is critical to the maintenance of retinal function. Many retinopathies such as age-related macular degeneration (AMD) are caused by the degeneration or malfunction of the RPE cell layer. Replacement of diseased RPE with healthy, stem cell-derived RPE is a potential therapeutic strategy for treating AMD. Human embryonic stem cells (hESCs) differentiated into RPE progeny have the potential to provide an unlimited supply of cells for transplantation, but challenges around scalability and efficiency of the differentiation process still remain. Using hESC-derived RPE as a cellular model, we sought to understand mechanisms that could be modulated to increase RPE yield after differentiation. We show that RPE epithelialization is a density-dependent process, and cells seeded at low density fail to epithelialize. We demonstrate that activation of the cAMP pathway increases proliferation of dissociated RPE in culture, in part through inhibition of transforming growth factor-b (TGF-b) signaling. This results in enhanced uptake of epithelial identity, even in cultures seeded at low density. In line with these findings, targeted manipulation of the TGF-b pathway with small molecules produces an increase in efficiency of RPE re-epithelialization. Taken together, these data highlight mechanisms that promote epithelial fate acquisition in stem cellderived RPE. Modulation of these pathways has the potential to favorably impact scalability and clinical translation of hESC-derived RPE as a cell therapy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5: 925-937 SIGNIFICANCE Stem cell-derived retinal pigment epithelium (RPE) is currently being evaluated as a cell-replacement therapy for macular degeneration. This work shows that the process of generating RPE in vitro is regulated by the cAMP and transforming growth factor-b signaling pathway. Modulation of these pathways by small molecules, as identified by phenotypic screening, leads to an increased efficiency of generating RPE cells with a higher yield. This can have a potential impact on manufacturing transplantation-ready cells at large scale and is advantageous for clinical studies using this approach in the future.

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Section: Discussionmentioning

confidence: 75%

Section: Increasing Camp Levels Promotes Acquisition Of Rpe Identity mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

Choudhary

Gutteridge

Impey

et al. 2016

Stem Cells Translational Medicine

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mentioning

confidence: 99%

“…It is noteworthy that agents that significantly increase intracellular levels of cAMP are also inhibitors of RPE cell migration. 17 Recent studies have shown that ADM inhibit platelet-derived growth factor (PDGF)-BB and fetal calf serum (FCS)-induced smooth muscle cell (SMC) migration in a concentration-dependent manner. 18 These data suggest that ADM may be implicated in the early stages of PVR, which involve the migration of RPE cells.…”

mentioning

confidence: 99%

Adrenomedullin Affects Two Signal Transduction Pathways and the Migration in Retinal Pigment Epithelial Cells

Huang

Wang

Yuan

et al. 2004

Investigative Ophthalmology & Visual Science

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ADM inhibits the migration of RPE cells in vitro by a mechanism that involves the reciprocal upregulation of cAMP and downregulation of cGMP, in association with reductions in [Ca2+]i. ADM-mediated fluctuations in [Ca2+]i, which are well known to be involved in cell migration, appear to be regulated in part by mechanisms involving cAMP synthase. Thus, it appears that ADM acts as a constitutive regulatory system to control aberrant RPE cell behavior and specific migration in response to inflammatory mediators.

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Intraocular extracellular cyclic nucleotide concentrations: the influence of vitreous surgery

Dalma-Weiszhauz

Blumenkranz

Hartzer

et al. 1993

Graefe's Arch Clin Exp Ophthalmol

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Levels of cAMP (23.1 pmol/ml) and cGMP (22.6 pmol/ml) are nearly equal in normal rabbit vitreous, although aqueous cAMP levels (29.9 pmol/ml) are 10 times higher than aqueous cGMP levels (2.6 pmol/ml) (P < 0.01). Intravitreal cAMP values decrease slightly 1 week after vitrectomy and lensectomy and return to normal whether the retina is attached, detached, or surgically removed. In contrast, intravitreal cGMP levels are profoundly depressed at 7 days (approximating normal aqueous levels) and are more than 50% lower than normal 30-42 days after surgery. The presence of these cyclic nucleotides in intraocular fluid and their responsiveness after surgery may signify a potential regulatory role in the physiologic responses of the eye to retinal detachment and its repair.

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Cyclic 3',5'-Adenosine Monophosphate Modulates Retinal Pigment Epithelial Cell Migration In Vitro

Cited by 12 publications

References 19 publications

Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

Targeting the cAMP and Transforming Growth Factor-β Pathway Increases Proliferation to Promote Re-Epithelialization of Human Stem Cell-Derived Retinal Pigment Epithelium

Adrenomedullin Affects Two Signal Transduction Pathways and the Migration in Retinal Pigment Epithelial Cells

Intraocular extracellular cyclic nucleotide concentrations: the influence of vitreous surgery

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