从自组织的人视网膜组织中产生纤毛边缘样干细胞龛。

Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue.

机构信息

1] Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, 2-2-3 Manatojima-Minamimachi, Chuo, Kobe 650-0047, Japan [2] Human Stem Cell Technology Unit, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo, Kobe 650-0047, Japan [3] Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-naka, Konohana, Osaka 554-8558, Japan.

1] Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, 2-2-3 Manatojima-Minamimachi, Chuo, Kobe 650-0047, Japan [2] Department of Endocrinology and Diabetes, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa, Nagoya 466-8550, Japan.

出版信息

Nat Commun. 2015 Feb 19;6:6286. doi: 10.1038/ncomms7286.

DOI:10.1038/ncomms7286

PMID:25695148

Abstract

In the developing neural retina (NR), multipotent stem cells within the ciliary margin (CM) contribute to de novo retinal tissue growth. We recently reported the ability of human embryonic stem cells (hESCs) to self-organize stratified NR using a three-dimensional culture technique. Here we report the emergence of CM-like stem cell niches within human retinal tissue. First, we developed a culture method for selective NR differentiation by timed BMP4 treatment. We then found that inhibiting GSK3 and FGFR induced the transition from NR tissue to retinal pigment epithelium (RPE), and that removing this inhibition facilitated the reversion of this RPE-like tissue back to the NR fate. This step-wise induction-reversal method generated tissue aggregates with RPE at the margin of central-peripherally polarized NR. We demonstrate that the NR-RPE boundary tissue further self-organizes a niche for CM stem cells that functions to expand the NR peripherally by de novo progenitor generation.

摘要

在发育中的神经视网膜 (NR) 中，睫状缘 (CM) 内的多能干细胞有助于新的视网膜组织生长。我们最近报道了人胚胎干细胞 (hESC) 使用三维培养技术自组织分层 NR 的能力。在这里，我们报告了人视网膜组织中 CM 样干细胞龛的出现。首先，我们开发了一种通过定时 BMP4 处理进行选择性 NR 分化的培养方法。然后我们发现，抑制 GSK3 和 FGFR 诱导 NR 组织向视网膜色素上皮 (RPE) 的转化，而去除这种抑制促进了这种 RPE 样组织向 NR 命运的逆转。这种逐步诱导-逆转方法生成了具有中央-外周极化 NR 边缘处 RPE 的组织聚集体。我们证明，NR-RPE 边界组织进一步自组织为 CM 干细胞的龛位，通过新的祖细胞生成来实现 NR 的外周扩张。