Photoreceptor laminin drives differentiation of human pluripotent stem cells to photoreceptor progenitors that partially restore retina function.
cell-based therapeutics
photoreceptor progenitors
pluripotent embryonic stem cells
retina-specific laminin isoform
synaptic connectivity
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
07
01
2022
revised:
12
07
2022
accepted:
21
12
2022
pmc-release:
01
03
2024
pubmed:
14
1
2023
medline:
7
3
2023
entrez:
13
1
2023
Statut:
ppublish
Résumé
Blindness caused by advanced stages of inherited retinal diseases and age-related macular degeneration are characterized by photoreceptor loss. Cell therapy involving replacement with functional photoreceptor-like cells generated from human pluripotent stem cells holds great promise. Here, we generated a human recombinant retina-specific laminin isoform, LN523, and demonstrated the role in promoting the differentiation of human embryonic stem cells into photoreceptor progenitors. This chemically defined and xenogen-free method enables reproducible production of photoreceptor progenitors within 32 days. We observed that the transplantation into rd10 mice were able to protect the host photoreceptor outer nuclear layer (ONL) up to 2 weeks post transplantation as measured by full-field electroretinogram. At 4 weeks post transplantation, the engrafted cells were found to survive, mature, and associate with the host's rod bipolar cells. Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses. Post-transplanted rabbit model also provided congruent evidence for synaptic connectivity with the degenerated host retina. The results may pave the way for the development of stem cell-based therapeutics for retina degeneration.
Identifiants
pubmed: 36638800
pii: S1525-0016(22)00716-X
doi: 10.1016/j.ymthe.2022.12.012
pmc: PMC10014235
pii:
doi:
Substances chimiques
Laminin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
825-846Informations de copyright
Copyright © 2022 Duke-NUS Medical School. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests K.T. is co-founder and shareholder in BioLamina. K.T. and H.G.T. are co-founders of Alder Therapeutics AB. Other authors declare no competing interests.
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