TIMP-3 Is Expressed in the Human Retinal Pigment Epithelium

Ruíz, Alexis Lorenzo; Peterson, Brett; Bok, Dean

doi:10.1006/bbrc.1996.1379

Cited by 52 publications

(34 citation statements)

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“…Experiments on SFD and DHRD hiPSC-RPE cultures had thus far demonstrated that molecular alterations limited to RPE cells alone were sufficient for drusen formation in monogenic maculopathies in which the affected gene (TIMP3, EFEMP1) is expressed predominantly by RPE cells (2,32). To further assess the sensitivity of hiPSC-RPE to capture a maculopathy-relevant phenotype, we next chose to investigate the origin of drusen development in a pedigree with the same disease phenotype as DHRD but with an unidentified genetic defect.…”

Section: Col4 Levels Are Higher In Ecm Isolated From Sfd and Dhrd Hipmentioning

confidence: 99%

“…Given that drusen in macular degeneration patient eyes are lipoproteinaceous deposits underlying RPE cells, we next evaluated if sub-RPE deposits in SFD and DHRD hiPSC-RPE in culture were also rich in neutral lipids and the RPE-synthesized drusen proteins APOE, CRYAA/CRYAB, and TIMP3 (32)(33)(34)(35). Consistent with published studies on mammalian RPE (14,36), staining of hiPSC-RPE cultures with Nile red demonstrated the presence of neutral lipids in Ctrl, SFD, and DHRD hiPSC-RPE cultures (Fig.…”

Section: The Composition Of Basal Deposits Varies In Sfd and Dhrd Hipmentioning

confidence: 99%

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Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Galloway

Dalvi

Hung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

122

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Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid-and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.human induced pluripotent stem cells | retinal pigment epithelium | macular dystrophies | drusen | sub-RPE deposits M aculopathies are a major cause of blindness, with agerelated macular degeneration (AMD) being the leading cause of irreversible vision loss in adults in the United States. Histopathological and clinical studies have shown that AMD and a subset of inherited macular dystrophies (MDs) share extensive phenotypic and clinical similarities (1-4). Specifically, AMD and related MDs have a cumulative etiology with adult onset of signs and symptoms and similar disease presentation including drusen formation, extracellular matrix (ECM) protein accumulation, thickening of Bruch's membrane, development of choroidal neovascularization, retinal pigment epithelium (RPE) atrophy, and ultimately the loss of vision (1-5). Although, the major pathological manifestations in these maculopathies are localized to the RPE-ECM interface in the retina, the multifactorial nature of these diseases, including the involvement of multiple retinal cell layers (photoreceptors, RPE, and choriocapillaris) (3, 6-9) and environmental risk factors (e.g., cigarette smoke) (10), has complicated the pursuit of t...

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Section: Col4 Levels Are Higher In Ecm Isolated From Sfd and Dhrd Hipmentioning

confidence: 99%

Section: The Composition Of Basal Deposits Varies In Sfd and Dhrd Hipmentioning

confidence: 99%

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Galloway

Dalvi

Hung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

122

View full text Add to dashboard Cite

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“…Within the eye, we, like others, found evidence of high levels of TIMP3 expression in the RPE layer of the eye (Alexander et al, 1990;Della et al, 1996;Fariss et al, 1997;Ruiz et al, 1996). This location corresponds to the site thought to be involved in SFD (Della et al, 1996;Fariss et al, 1997;Ruiz et al, 1996).…”

Section: Discussionmentioning

confidence: 57%

“…This location corresponds to the site thought to be involved in SFD (Della et al, 1996;Fariss et al, 1997;Ruiz et al, 1996). In SFD, it is thought that single point mutations in TIMP3 lead to Expression is observed in the choroid plexus in the lateral ventricle (A), developing bones including humerus (B; arrow depicts lacZ expression in the periphery of the bone), vertebrae (C; arrows), eye sockets (D; arrow; asterisk labels choroid plexus in the lumen of the fourth ventricle) and between developing bones of the feet (E) in all lines of mice at gd 14/15.…”

Section: Discussionmentioning

confidence: 88%

“…Tissue-specific expression of TIMP3 has been characterized in a number of in vitro studies. Approaches used include protein assays (Alexander et al, 1990(Alexander et al, , 1991(Alexander et al, , 1996, mRNA analyses (Apte et al, 1994a,b;Della et al, 1996;Hurskainen et al, 1996;Jomary et al, 1995;Leco et al, 1994;Ruiz et al, 1996), and immunohistochemistry (Fariss et al, 1997;Gupta et al, 1997;Kishnani et al, 1994). The in vitro effects of TIMP3 overexpression on growth characteristics and malignant potential of tumor cells (Bian et al, 1996;Sun et al, 1996), and on capillary endothelial cell proliferation and migration (Johnson et al, 1994;Moses et al, 1990) suggest a role of this gene in oncogenesis and neovascularization.…”

Section: Introductionmentioning

confidence: 98%

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Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene

Zeng

Rosborough

et al. 1998

Dev. Dyn.

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A complex interplay between enzymes involved in extracellular matrix formation and their inhibitors is thought to control organogenesis during mammalian development. Disturbance of this balance may result in a wide range of diseases, including macular degeneration, arthritis, and tumor metastases. In order to define elements which may be involved in regulating human tissue inhibitor of metalloproteinase 3 (TIMP3) expression, we isolated and sequenced a clone containing 1315 bp of the 5′‐upstream region of the human TIMP‐3‐encoding gene. A 1.2 kb fragment of this clone, which contains multiple motifs which are binding sites for known transcription factors, was used to drive expression of the lacZ reporter gene in multiple lines of transgenic mice. TIMP3 promoter activity, detected through β‐galactosidase histochemical assay, was observed at high levels in selected tissues, the identity of which varied according to developmental stage. TIMP3 promoter activity was detected at embryonic and early postnatal stages in tissues undergoing extensive remodeling, such as developing somites, bones and joints, choroid plexus, webs between the digits, and the spongiotrophoblastic portion of the placenta. In adulthood, TIMP3 promoter activity was restricted to a few tissues which exhibit high metabolic activity or rapid turnover. These include the retinal pigment epithelium (RPE), cells of the kidney cortex, hair follicles, gingiva, ovarian follicles, and testis. The results suggest that TIMP3 expression plays an active role in developmental patterning and in the maintenance of specific differentiated tissues. Dev. Dyn. 1998;211:228‐237. © 1998 Wiley‐Liss, Inc.

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Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Zarbin¹

2004

Arch Ophthalmol

910

697

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To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD).Methods: Review of the English-language literature.Results: Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and(5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient's susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously.Conclusions: Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

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TIMP-3 Is Expressed in the Human Retinal Pigment Epithelium

Cited by 52 publications

References 0 publications

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

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