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

Chad A. Galloway, Sonal Dalvi, Sandy S.C. Hung, Leslie A. MacDonald, Lisa R. Latchney, Raymond C.B. Wong, Robyn H. Guymer, David A. Mackey, David S. Williams, Mina M. Chung, David M. Gamm, Alice Pébay, Alex W. Hewitt, Ruchira Singh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E8214-E8223
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number39
DOIs
Publication statusPublished - 26 Sep 2017

Fingerprint

Induced Pluripotent Stem Cells
Retinal Pigment Epithelium
Macular Degeneration
Extracellular Matrix
Pathology
Serum
Genes
Up-Regulation
Lipids
Doyne honeycomb retinal dystrophy
Proteins

Cite this

Galloway, C. A., Dalvi, S., Hung, S. S. C., MacDonald, L. A., Latchney, L. R., Wong, R. C. B., ... Singh, R. (2017). Drusen in patient-derived hiPSC-RPE models of macular dystrophies. Proceedings of the National Academy of Sciences of the United States of America, 114(39), E8214-E8223. https://doi.org/10.1073/pnas.1710430114
Galloway, Chad A. ; Dalvi, Sonal ; Hung, Sandy S.C. ; MacDonald, Leslie A. ; Latchney, Lisa R. ; Wong, Raymond C.B. ; Guymer, Robyn H. ; Mackey, David A. ; Williams, David S. ; Chung, Mina M. ; Gamm, David M. ; Pébay, Alice ; Hewitt, Alex W. ; Singh, Ruchira. / Drusen in patient-derived hiPSC-RPE models of macular dystrophies. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 39. pp. E8214-E8223.
@article{17c8b21fafad442ea938b8cdf1d81e10,
title = "Drusen in patient-derived hiPSC-RPE models of macular dystrophies",
abstract = "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.",
keywords = "Drusen, Human induced pluripotent stem cells, Macular dystrophies, Retinal pigment epithelium, Sub-RPE deposits",
author = "Galloway, {Chad A.} and Sonal Dalvi and Hung, {Sandy S.C.} and MacDonald, {Leslie A.} and Latchney, {Lisa R.} and Wong, {Raymond C.B.} and Guymer, {Robyn H.} and Mackey, {David A.} and Williams, {David S.} and Chung, {Mina M.} and Gamm, {David M.} and Alice P{\'e}bay and Hewitt, {Alex W.} and Ruchira Singh",
year = "2017",
month = "9",
day = "26",
doi = "10.1073/pnas.1710430114",
language = "English",
volume = "114",
pages = "E8214--E8223",
journal = "National Academy of Sciences, Proceedings",
issn = "0027-8424",
publisher = "NATL ACAD SCIENCES",
number = "39",

}

Galloway, CA, Dalvi, S, Hung, SSC, MacDonald, LA, Latchney, LR, Wong, RCB, Guymer, RH, Mackey, DA, Williams, DS, Chung, MM, Gamm, DM, Pébay, A, Hewitt, AW & Singh, R 2017, 'Drusen in patient-derived hiPSC-RPE models of macular dystrophies' Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 39, pp. E8214-E8223. https://doi.org/10.1073/pnas.1710430114

Drusen in patient-derived hiPSC-RPE models of macular dystrophies. / Galloway, Chad A.; Dalvi, Sonal; Hung, Sandy S.C.; MacDonald, Leslie A.; Latchney, Lisa R.; Wong, Raymond C.B.; Guymer, Robyn H.; Mackey, David A.; Williams, David S.; Chung, Mina M.; Gamm, David M.; Pébay, Alice; Hewitt, Alex W.; Singh, Ruchira.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 39, 26.09.2017, p. E8214-E8223.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Drusen in patient-derived hiPSC-RPE models of macular dystrophies

AU - Galloway, Chad A.

AU - Dalvi, Sonal

AU - Hung, Sandy S.C.

AU - MacDonald, Leslie A.

AU - Latchney, Lisa R.

AU - Wong, Raymond C.B.

AU - Guymer, Robyn H.

AU - Mackey, David A.

AU - Williams, David S.

AU - Chung, Mina M.

AU - Gamm, David M.

AU - Pébay, Alice

AU - Hewitt, Alex W.

AU - Singh, Ruchira

PY - 2017/9/26

Y1 - 2017/9/26

N2 - 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.

AB - 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.

KW - Drusen

KW - Human induced pluripotent stem cells

KW - Macular dystrophies

KW - Retinal pigment epithelium

KW - Sub-RPE deposits

UR - http://www.scopus.com/inward/record.url?scp=85029907814&partnerID=8YFLogxK

U2 - 10.1073/pnas.1710430114

DO - 10.1073/pnas.1710430114

M3 - Article

VL - 114

SP - E8214-E8223

JO - National Academy of Sciences, Proceedings

JF - National Academy of Sciences, Proceedings

SN - 0027-8424

IS - 39

ER -