One of the most important potential uses of embryonic stem cells and induced pluripotent stem cell research is in the development of disease models. Although many diseases can be modeled in mice, others are difficult or impossible to adequately model in non-human organisms for a variety of reasons. In the retina, for example, there are mouse models for many inherited degenerations, but these have been more difficult to generate for diseases like macular degeneration and many forms of Usher's disease. Therefore, disease models from human patient iPS cells would be of great utility in retinal research. In the past six years, our group, and others, have developed protocols for efficient production of retinal cells from human ESCs and iPSCs. The early stages of retinal development are extremely well recapitulated by our protocol of directed differentiation of hESC cells;however, the cells fail to attain the level of expression of markers that we observe in the late stages of human fetal or postnatal development, even with prolonged culture periods. Therefore, a significant challenge for creation of disease models from iPSCs will be to better understand and promote the progression of the cultured cells to mature stages of retina. The mechanisms that control the developmental timing of retinal progenitor cells are not clear;however, recent evidence from our lab shows a key role for miRNAs. Specifically, we found that the loss of Dicer in retinal progenitor cells leads to their failure to progress from the """"""""early"""""""" state to the """"""""late"""""""" state. We therefore hypothesize (1) that miRNAs regulate developmental timing in retinal progenitor cells and (2) that misregulation of the heterochronic pathway in ESC-derived retinal cells accounts for their failure to progress in vitro at the same rate as in vivo. We propose to test these hypotheses with the following specific aims.
Aim 1 : Determine whether the expression of specific miRNAs (and the genes they regulate) correlates with the progression of retinal progenitors from the early to late stage.
Aim 2. Determine whether the developmental progression of mouse ESC/iPSC-derived retinal progenitors is controlled by stage-specific progenitor miRNAs.
Aim 3. Determine whether the developmental progression of human ESC derived retinal progenitors can be accelerated by stage-specific miRNAs. The results of these studies will enable us to better control the development of hESC-derived retinal cells and produce more appropriate models of retinal disease.
The loss of sight from degenerative diseases of the retina is a major human health problem. Millions of Americans are affected with these diseases and since many are age-related, the number of affected individuals is expected to increase as the population ages. Our research is aimed at determining whether stem cells can be used to treat these diseases, both through cell therapy and disease modeling with induced pluripotent cells.
|Palpant, Nathan J; Pabon, Lil; Friedman, Clayton E et al. (2017) Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells. Nat Protoc 12:15-31|
|Kim, Yong Kyun; Refaeli, Ido; Brooks, Craig R et al. (2017) Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development. Stem Cells 35:2366-2378|
|Kadota, Shin; Pabon, Lil; Reinecke, Hans et al. (2017) In Vivo Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Neonatal and Adult Rat Hearts. Stem Cell Reports 8:278-289|
|Palpant, Nathan J; Wang, Yuliang; Hadland, Brandon et al. (2017) Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis. Cell Rep 20:1597-1608|
|Rabinowitz, Jeremy S; Robitaille, Aaron M; Wang, Yuliang et al. (2017) Transcriptomic, proteomic, and metabolomic landscape of positional memory in the caudal fin of zebrafish. Proc Natl Acad Sci U S A 114:E717-E726|
|Artoni, Filippo; Kreipke, Rebecca E; Palmeira, Ondina et al. (2017) Loss of foxo rescues stem cell aging in Drosophila germ line. Elife 6:|
|Moody, James D; Levy, Shiri; Mathieu, Julie et al. (2017) First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. Proc Natl Acad Sci U S A 114:10125-10130|
|Nakamura, Paul A; Shimchuk, Andy A; Tang, Shibing et al. (2017) Small molecule Photoregulin3 prevents retinal degeneration in the RhoP23H mouse model of retinitis pigmentosa. Elife 6:|
|Ware, Carol B (2017) Concise Review: Lessons from Naïve Human Pluripotent Cells. Stem Cells 35:35-41|
|Mathieu, Julie; Ruohola-Baker, Hannele (2017) Metabolic remodeling during the loss and acquisition of pluripotency. Development 144:541-551|
Showing the most recent 10 out of 111 publications