Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells

Julien Maruotti, Srinivas R. Sripathi, Kapil Bharti, John Fuller, Karl J. Wahlin, Vinod Ranganathan, Valentin M. Sluch, Cynthia A. Berlinicke, Janine Davis, Catherine Kim, Lijun Zhao, Jun Wan, Jiang Qian, Barbara Corneo, Sally Temple, Ramin Dubey, Bogdan Z. Olenyuk, Imran Bhutto, Gerard A. Lutty, Donald J. Zack

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related macular degeneration (AMD) is associated with dysfunction and death of retinal pigment epithelial (RPE) cells. Cell-based approaches using RPE-like cells derived from human pluripotent stem cells (hPSCs) are being developed for AMD treatment. However, most efficient RPE differentiation protocols rely on complex, stepwise treatments and addition of growth factors, whereas small-molecule-only approaches developed to date display reduced yields. To identify new compounds that promote RPE differentiation, we developed and performed a high-throughput quantitative PCR screen complemented by a novel orthogonal human induced pluripotent stem cell (hiPSC)-based RPE reporter assay. Chetomin, an inhibitor of hypoxia-inducible factors, was found to strongly increase RPE differentiation; combination with nicotinamide resulted in conversion of over one-half of the differentiating cells into RPE. Single passage of the whole culture yielded a highly pure hPSC-RPE cell population that displayed many of the morphological, molecular, and functional characteristics of native RPE.

Original languageEnglish (US)
Pages (from-to)10950-10955
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number35
DOIs
StatePublished - Sep 1 2015

Keywords

  • Age-related macular degeneration
  • Differentiation
  • High-throughput screening
  • Pluripotent stem cells
  • Retinal pigment epithelium

ASJC Scopus subject areas

  • General

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