TY - JOUR
T1 - Neural stem cell properties of Müller glia in the mammalian retina
T2 - Regulation by Notch and Wnt signaling
AU - Das, Ani V.
AU - Mallya, Kavita B.
AU - Zhao, Xing
AU - Ahmad, Faraz
AU - Bhattacharya, Sumitra
AU - Thoreson, Wallace B.
AU - Hegde, Ganapati V.
AU - Ahmad, Iqbal
N1 - Funding Information:
We would like to thank Dr. Spyros Artavanis-Tsakonas for the Notch1 antibody, Dr. Shinichi Nakagawa for the Wnt2b construct, Dr. Jeremy Nathans for the FzdCRD constructs and Dr. Anuja Ghorpade for the Iba-1 antibody. Thanks are due to Dr. Jim Rogers for his valuable advice and guidance on LDA, Drs. Graham Sharp and Gregory Bennett for critiquing the manuscript and helpful suggestions, Dr. Kenneth Cowan for the adenovirus vectors and Gaurav Sahay for the technical assistance. This work was supported by the Nebraska Tobacco Settlement Biomedical Research Development, NIH and Research to Prevent Blindness.
PY - 2006/11/1
Y1 - 2006/11/1
N2 - The retina in adult mammals, unlike those in lower vertebrates such as fish and amphibians, is not known to support neurogenesis. However, when injured, the adult mammalian retina displays neurogenic changes, raising the possibility that neurogenic potential may be evolutionarily conserved and could be exploited for regenerative therapy. Here, we show that Müller cells, when retrospectively enriched from the normal retina, like their radial glial counterparts in the central nervous system (CNS), display cardinal features of neural stem cells (NSCs), i.e., they self-renew and generate all three basic cell types of the CNS. In addition, they possess the potential to generate retinal neurons, both in vitro and in vivo. We also provide direct evidence, by transplanting prospectively enriched injury-activated Müller cells into normal eye, that Müller cells have neurogenic potential and can generate retinal neurons, confirming a hypothesis, first proposed in lower vertebrates. This potential is likely due to the NSC nature of Müller cells that remains dormant under the constraint of non-neurogenic environment of the adult normal retina. Additionally, we demonstrate that the mechanism of activating the dormant stem cell properties in Müller cells involves Wnt and Notch pathways. Together, these results identify Müller cells as latent NSCs in the mammalian retina and hence, may serve as a potential target for cellular manipulation for treating retinal degeneration.
AB - The retina in adult mammals, unlike those in lower vertebrates such as fish and amphibians, is not known to support neurogenesis. However, when injured, the adult mammalian retina displays neurogenic changes, raising the possibility that neurogenic potential may be evolutionarily conserved and could be exploited for regenerative therapy. Here, we show that Müller cells, when retrospectively enriched from the normal retina, like their radial glial counterparts in the central nervous system (CNS), display cardinal features of neural stem cells (NSCs), i.e., they self-renew and generate all three basic cell types of the CNS. In addition, they possess the potential to generate retinal neurons, both in vitro and in vivo. We also provide direct evidence, by transplanting prospectively enriched injury-activated Müller cells into normal eye, that Müller cells have neurogenic potential and can generate retinal neurons, confirming a hypothesis, first proposed in lower vertebrates. This potential is likely due to the NSC nature of Müller cells that remains dormant under the constraint of non-neurogenic environment of the adult normal retina. Additionally, we demonstrate that the mechanism of activating the dormant stem cell properties in Müller cells involves Wnt and Notch pathways. Together, these results identify Müller cells as latent NSCs in the mammalian retina and hence, may serve as a potential target for cellular manipulation for treating retinal degeneration.
KW - Chemical injury
KW - Müller cells
KW - Notch signaling
KW - Progenitors
KW - Retina
KW - Stem cells
KW - Wnt signaling
UR - http://www.scopus.com/inward/record.url?scp=33749655904&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749655904&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2006.07.029
DO - 10.1016/j.ydbio.2006.07.029
M3 - Article
C2 - 16949068
AN - SCOPUS:33749655904
SN - 0012-1606
VL - 299
SP - 283
EP - 302
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -