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.
|Ware, Carol B; Nelson, Angelique M; Mecham, Brigham et al. (2014) Derivation of naive human embryonic stem cells. Proc Natl Acad Sci U S A 111:4484-9|
|Murry, Charles E; Chong, James J H; Laflamme, Michael A (2014) Letter by Murry et al regarding article, "Embryonic stem cell-derived cardiac myocytes are not ready for human trials". Circ Res 115:e28-9|
|Tung, Jason C; Paige, Sharon L; Ratner, Buddy D et al. (2014) Engineered biomaterials control differentiation and proliferation of human-embryonic-stem-cell-derived cardiomyocytes via timed Notch activation. Stem Cell Reports 2:271-81|
|Yang, Xiulan; Rodriguez, Marita; Pabon, Lil et al. (2014) Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J Mol Cell Cardiol 72:296-304|
|Naumova, Anna V; Modo, Michel; Moore, Anna et al. (2014) Clinical imaging in regenerative medicine. Nat Biotechnol 32:804-18|
|Guan, Xuan; Mack, David L; Moreno, Claudia M et al. (2014) Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery. Stem Cell Res 12:467-80|
|Mathieu, Julie; Zhou, Wenyu; Xing, Yalan et al. (2014) Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell 14:592-605|
|Nguyen-Tran, Diem-Hang; Hait, Nitai C; Sperber, Henrik et al. (2014) Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy. Dis Model Mech 7:41-54|
|Chong, James J H; Yang, Xiulan; Don, Creighton W et al. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273-7|
|Jiao, Alex; Trosper, Nicole E; Yang, Hee Seok et al. (2014) Thermoresponsive nanofabricated substratum for the engineering of three-dimensional tissues with layer-by-layer architectural control. ACS Nano 8:4430-9|
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