Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice

Abstract

Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial-mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor-b (TGF-b) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF-b and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of a-smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF-b signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR.

Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

“…FITC-conjugated secondary antibodies were used to visualize the specific immunoreaction as previously reported. [34][35][36] Results…”

“…34 Briefly, under general anesthesia by pentobarbital sodium, i.p., a linear incision was made in the central cornea and the crystalline lens was removed. After the vitreous cavity was filled with 1.0% hyaluronan, the retina was gently removed with forceps without damaging the pigment epithelium.…”

TGFβ pathobiology in the eye

“…Indeed, loss of Smad3 attenuates PVR in vivo, 87 and Smad7 gene introduction actually does suppress PVR in mice (S Saika, unpublished data, 2005).…”

Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali injury model in mice

“…[12][13][14] Blocking signaling mediated by Smad2/3, the cytoplasmic signaling intermediates specific for TGF-b/ activin, is effective in inhibiting injury-induced tissue fibrosis in many tissues, such as skin, kidney, and the lens and retina of the eye. [15][16][17][18][19][20][21][22][23][24][25][26] We have recently revealed that both topical administration of SN50, an inhibitor of NF-kB signal, and adenoviral gene introduction of the Smad7, an inhibitory Smad that blocks Smads2/3, block tissue destruction in an alkali-burned cornea in mice (Saika et al, 2004 24,35 ).…”