FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice
(2016) In Proceedings of the National Academy of Sciences of the United States of America 113(30). p.8514-8519- Abstract
We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts... (More)
We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.
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- author
- Ahlenius, Henrik LU ; Chanda, Soham ; Webb, Ashley E. ; Yousif, Issa ; Karmazin, Jesse ; Prusiner, Stanley B. ; Brunet, Anne ; Südhof, Thomas C. and Wernig, Marius
- publishing date
- 2016-07-26
- type
- Contribution to journal
- publication status
- published
- keywords
- Aging, Induced neuronal cells, Reprogramming
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 113
- issue
- 30
- pages
- 8514 - 8519
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:84979584060
- pmid:27402759
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.1607079113
- language
- English
- LU publication?
- no
- id
- 1dd3f291-6012-4877-8878-e3556a1538f7
- date added to LUP
- 2025-08-26 11:19:05
- date last changed
- 2025-08-26 12:50:30
@article{1dd3f291-6012-4877-8878-e3556a1538f7,
abstract = {{<p>We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.</p>}},
author = {{Ahlenius, Henrik and Chanda, Soham and Webb, Ashley E. and Yousif, Issa and Karmazin, Jesse and Prusiner, Stanley B. and Brunet, Anne and Südhof, Thomas C. and Wernig, Marius}},
issn = {{0027-8424}},
keywords = {{Aging; Induced neuronal cells; Reprogramming}},
language = {{eng}},
month = {{07}},
number = {{30}},
pages = {{8514--8519}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice}},
url = {{http://dx.doi.org/10.1073/pnas.1607079113}},
doi = {{10.1073/pnas.1607079113}},
volume = {{113}},
year = {{2016}},
}