作者: Wang, Jie ; Liu, Juping ; Shao, Yan ; Huang, Xinyuan ; Li, Xiaorong ; Wang, Manqiao ; Li, Qingbo ; Xu, Shuzhan ; Luan, Rong ; Gong, Yi ; Xu, Manhong

This study investigates the role of bone morphogenetic protein-4 (BMP4) in age-related macular degeneration (AMD), with a focus on its effects on subretinal fibrosis and choroidal neovascularization (CNV). Using a mouse model of laser-induced CNV, we found that BMP4 expression was significantly elevated in CNV lesions. BMP4 was shown to promote fibroblast proliferation and their differentiation into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA). Additionally, BMP4 promoted the transition of endothelial progenitor cells (EPCs) into endothelial cells (ECs), a process that was modulated by mitochondrial function. Intravitreal administration of Noggin, a BMP4 inhibitor, significantly reduced CNV lesion volume and decreased the expression of CD31 and α-SMA, suggesting a decrease in neovascularization and fibrosis. These findings underscore BMP4's critical role in AMD pathogenesis by driving both angiogenesis and fibrosis. Targeting BMP4 with Noggin presents a promising therapeutic approach for AMD, addressing both neovascularization and fibrosis in a single intervention, and highlights BMP4 as a potential novel target for AMD therapy.

2022-03-01·Biochemistry and Biophysics Reports

Slow diffusion on the monolayer culture enhances auto/paracrine effects of Noggin in differentiation of human iPS cells induced by BMP

Article

作者: Okajima, Riho ; Nakatani, Eri ; Ohnuma, Kiyoshi

Auto/paracrine factors secreted from cells affect differentiation of human pluripotent stem cells (hPSCs). However, the molecular mechanisms underlying the role of secreted factors are not well known. We previously showed that pattern formation in hPSCs induced by BMP4 could be reproduced by a simple reaction-diffusion of BMP and Noggin, a cell-secreted BMP4 inhibitor. However, the amount of Noggin secreted is unknown. In this study, we measured the concentration of Noggin secreted during the differentiation of hPSCs induced by BMP4. The Noggin concentration in the supernatant before and after differentiation was constant at approximately 0.69 ng/mL, which is approximately 50-200 times less than expected in the model. To explain the difference between the experiment and model, we assumed that macromolecules such as heparan sulfate proteoglycan on the cell surface act as a diffusion barrier structure, where the diffusion slows down to 1/400. The model with the diffusion barrier structure reduced the Noggin concentration required to suppress differentiation in the static culture model. The model also qualitatively reproduced the pattern formation, in which only the upstream but not the downstream hPSCs were differentiated in a one-directional perfusion culture chamber, with a small change in the amount of secreted Noggin resulting in a large change in the differentiation position. These results suggest that the diffusion barrier on the cell surface might enhance the auto/paracrine effects on monolayer hPSC culture.

2019-03-01·Journal of Cellular and Molecular Medicine2区 · 医学

Neural induction of porcine‐induced pluripotent stem cells and further differentiation using glioblastoma‐cultured medium

2区 · 医学

ArticleOA

作者: Kim, Mirae ; Kim, Eunhye ; Park, Young Seok ; Kim, Jongpil ; Lee, Gabsang ; Hwang, Seon‐Ung ; Hyun, Sang‐Hwan

AbstractPrior to transplantation, preclinical study of safety and efficacy of neural progenitor cells (NPCs) is needed. Therefore, it is important to generate an efficient in vitro platform for neural cell differentiation in large animal models such as pigs. In this study, porcine‐induced pluripotent stem cells (iPSCs) were seeded at high cell density to a neural induction medium containing the dual Sma‐ and Mad‐related protein (SMAD) inhibitors, a TGF‐β inhibitor and BMP4 inhibitor. The dSMADi‐derived NPCs showed NPC markers such as PLAG1, NESTIN and VIMENTIN and higher mRNA expression of Sox1 compared to the control. The mRNA expression of HOXB4 was found to significantly increase in the retinoic acid‐treated group. NPCs propagated in vitro and generated neurospheres that are capable of further differentiation in neurons and glial cells. Gliobalstoma‐cultured medium including injury‐related cytokines treated porcine iPSC‐NPCs survive well in vitro and showed more neuronal marker expression compared to standard control medium. Collectively, the present study developed an efficient method for production of neural commitment of porcine iPSCs into NPCs.

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