TY - JOUR
T1 - Continuous non-cell autonomous reprogramming to generate retinal ganglion cells for glaucomatous neuropathy
AU - Parameswaran, Sowmya
AU - Dravid, Shashank Manohar
AU - Teotia, Pooja
AU - Krishnamoorthy, Raghu R.
AU - Qiu, Fang
AU - Toris, Carol
AU - Morrison, John
AU - Ahmad, Iqbal
N1 - Publisher Copyright:
© 2015 AlphaMed Press.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Glaucoma, where the retinal ganglion cells (RGCs) carrying the visual signals from the retina to the visual centers in the brain are progressively lost, is the most common cause of irreversible blindness. The management approaches, whether surgical, pharmacological, or neuroprotective do not reverse the degenerative changes. The stem cell approach to replace dead RGCs is a viable option but currently faces several barriers, such as the lack of a renewable, safe, and ethical source of RGCs that are functional and could establish contacts with bona fide targets. To address these barriers, we have derived RGCs from the easily accessible adult limbal cells, reprogrammed to pluripotency by a non-nucleic acid approach, thus circumventing the risk of insertional mutagenesis. The generation of RGCs from the induced pluripotent stem (iPS) cells, also accomplished non-cell autonomously, recapitulated the developmental mechanism, ensuring the predictability and stability of the acquired phenotype, comparable to that of native RGCs at biochemical, molecular, and functional levels. More importantly, the induced RGCs expressed axonal guidance molecules and demonstrated the potential to establish contacts with specific targets. Furthermore, when transplanted in the rat model of ocular hypertension, these cells incorporated into the host RGC layer and expressed RGC-specific markers. Transplantation of these cells in immune-deficient mice did not produce tumors. Together, our results posit retinal progenitors generated from non-nucleic acid-derived iPS cells as a safe and robust source of RGCs for replacing dead RGCs in glaucoma.
AB - Glaucoma, where the retinal ganglion cells (RGCs) carrying the visual signals from the retina to the visual centers in the brain are progressively lost, is the most common cause of irreversible blindness. The management approaches, whether surgical, pharmacological, or neuroprotective do not reverse the degenerative changes. The stem cell approach to replace dead RGCs is a viable option but currently faces several barriers, such as the lack of a renewable, safe, and ethical source of RGCs that are functional and could establish contacts with bona fide targets. To address these barriers, we have derived RGCs from the easily accessible adult limbal cells, reprogrammed to pluripotency by a non-nucleic acid approach, thus circumventing the risk of insertional mutagenesis. The generation of RGCs from the induced pluripotent stem (iPS) cells, also accomplished non-cell autonomously, recapitulated the developmental mechanism, ensuring the predictability and stability of the acquired phenotype, comparable to that of native RGCs at biochemical, molecular, and functional levels. More importantly, the induced RGCs expressed axonal guidance molecules and demonstrated the potential to establish contacts with specific targets. Furthermore, when transplanted in the rat model of ocular hypertension, these cells incorporated into the host RGC layer and expressed RGC-specific markers. Transplantation of these cells in immune-deficient mice did not produce tumors. Together, our results posit retinal progenitors generated from non-nucleic acid-derived iPS cells as a safe and robust source of RGCs for replacing dead RGCs in glaucoma.
KW - Glaucoma
KW - Induced pluripotent stem cells
KW - Non-cell autonomous
KW - Retinal ganglion cells
KW - Teratoma
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U2 - 10.1002/stem.1987
DO - 10.1002/stem.1987
M3 - Article
C2 - 25753398
AN - SCOPUS:84929791632
SN - 1066-5099
VL - 33
SP - 1743
EP - 1758
JO - STEM CELLS
JF - STEM CELLS
IS - 6
ER -