Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.

AIMS: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI. METHODS AND RESULTS: Reverse transcriptase-polymerized chain reaction and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts. CONCLUSIONS: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy

Agreement, repeatability, and reproducibility of quantitative retinal layer assessment using swept-source and spectral-domain optical coherence tomography in eyes with retinal diseases

PurposeTo evaluate the agreement and precision of retinal thickness measurements obtained using swept-source optical coherence tomography (SS-OCT) and spectral-domain OCT (SD-OCT) in healthy eyes and eyes with retinopathy.MethodsThis cross-sectional prospective study involved three DRI-OCT Triton (SS-OCT) and three 3D-OCT-1 Maestro (SD-OCT) devices. One of each device (Maestro and Triton) was paired with a single operator. Healthy subjects and patients with retinal diseases were recruited, with study eye and testing order randomized. At least 3 scans per eye were captured for wide scan (12 mm × 9 mm-Triton and Maestro) and macular cube scan (7 mm × 7 mm-Triton, 6 mm × 6 mm-Maestro). Thickness of the full retina, ganglion cell layer + inner plexiform layer (GCL+), and ganglion cell complex (GCL++) were obtained from wide scan and cube scans. Agreement of the measurements between the Triton and Maestro was evaluated by Bland–Altman analysis and Deming regression for each group. Repeatability and reproducibility were assessed using a two-way random effect analysis of variance (ANOVA) model for each parameter by group.ResultsTwenty-five healthy subjects (25 eyes) and 26 patients with retinal diseases (26 eyes), including, but not limited to, age-related macular degeneration, macular hole, and diabetic retinopathy were recruited. Overall, the measurement differences between Triton and Maestro were <6 μm (mean differences of full retina, GCL++, and GCL+ thickness were ≤5.5 μm, 1.3 μm, and 2.8 μm, respectively) and not statistically significant across the parameters. The repeatability and reproducibility estimates indicate high precision in both devices and groups. Across all the parameters, the repeatability limit was ≤7.6 μm for Triton and ≤12.7 μm for Maestro; reproducibility limit was ≤9.2 μm for Triton and ≤14.4 μm for Maestro. In eyes with retinal pathology, the repeatability coefficient of variation (CV)% was ≤2.6% for Triton and ≤3.4% for Maestro; reproducibility CV% was ≤3.3% for Triton and ≤3.5% for Maestro.ConclusionBoth Triton SS-OCT and Maestro SD-OCT provide reliable measurements of retinal thickness in healthy eyes and eyes with retinal diseases. Excellent agreement between the two devices indicates interoperability when testing healthy eyes or eyes with retinal pathology. These findings support the use of thickness measurements from Triton SS-OCT and Maestro SD-OCT in clinical practice

Bone marrow-derived cells in ocular neovascularization: contribution and mechanisms

Ocular neovascularization often leads to severe vision loss. The role of bone marrow-derived cells (BMCs) in the development of ocular neovascularization, and its significance, is increasingly being recognized. In this review, we discuss their contribution and the potential mechanisms that mediate the effect of BMCs on the progression of ocular neovascularization. The sequence of events by which BMCs participate in ocular neovascularization can be roughly divided into four phases, i.e., mobilization, migration, adhesion and differentiation. This process is delicately regulated and liable to be affected by multiple factors. Cytokines such as vascular endothelial growth factor, granulocyte colony-stimulating factor and erythropoietin are involved in the mobilization of BMCs. Studies have also demonstrated a key role of cytokines such as stromal cell-derived factor-1, tumor necrosis factor-α, as well as vascular endothelial growth factor, in regulating the migration of BMCs. The adhesion of BMCs is mainly regulated by vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and vascular endothelial cadherin. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. In addition, BMCs secrete cytokines that interact with the microenvironment of ocular neovascularization; their contribution to ocular neovascularization, especially choroidal neovascularization, can be aggravated by several risk factors. An extensive regulatory network is thought to modulate the role of BMCs in the development of ocular neovascularization. A comprehensive understanding of the involved mechanisms will help in the development of novel therapeutic strategies related to BMCs. In this review, we have limited the discussion to the recent progress in this field, especially the research conducted at our laboratory