Optimizing standardized lab-grown skin substitutes evidences a proliferation-differentiation switch based on ascorbic acid
Molina-Oviedo, Angie Katherine ; Sorrentino, Ilaria ; Clares-Pedrero, Irene ; Salamanca-Gonzalez, Celina ; Arevalo-Nuñez de Arenas, Eduardo ; Mazariegos, Marina S. LU
; Cabañas, Carlos
and Medraño-Fernandez, Iria
(2025)
In iScience
28(8).
- Abstract
Developing standardized bioengineered constructs that accurately replicate human skin is a largely sought-after goal. Pathways initiated at the nurturing interface with the dermal compartment have the potential to modulate the developing epidermal architecture. Here, we identified ascorbic acid, a dermis-donated metabolite, as key in modulating the phenotypical identity of immortalized keratinocytes. Priming monolayers with 2 μg/mL of the culture-stable derivative L-ascorbic acid 2-phosphate (A2P) led to the emergence of a basal-like phenotype within the cells, which showed increased clonogenicity, nuclear/cytoplasmic ratio, and upregulation of progenitor markers. Instead, surpassing this dose induced intracellular ascorbic acid... (More)
Developing standardized bioengineered constructs that accurately replicate human skin is a largely sought-after goal. Pathways initiated at the nurturing interface with the dermal compartment have the potential to modulate the developing epidermal architecture. Here, we identified ascorbic acid, a dermis-donated metabolite, as key in modulating the phenotypical identity of immortalized keratinocytes. Priming monolayers with 2 μg/mL of the culture-stable derivative L-ascorbic acid 2-phosphate (A2P) led to the emergence of a basal-like phenotype within the cells, which showed increased clonogenicity, nuclear/cytoplasmic ratio, and upregulation of progenitor markers. Instead, surpassing this dose induced intracellular ascorbic acid accumulation and promoted a motile status. In organotypic cultures, pre-incubation of founding keratinocytes with 2 μg/mL of A2P improved epithelial layering, whereas higher pretreatments resulted in poor stratification. These findings suggest that ascorbic acid levels in the self-renewing epithelium have a fundamental role in determining whether cells initially commit to differentiation, ultimately influencing regenerative outcomes.
(Less)
- author
- Molina-Oviedo, Angie Katherine
; Sorrentino, Ilaria
; Clares-Pedrero, Irene
; Salamanca-Gonzalez, Celina
; Arevalo-Nuñez de Arenas, Eduardo
; Mazariegos, Marina S.
LU
; Cabañas, Carlos
and Medraño-Fernandez, Iria
- organization
- publishing date
- 2025-08-15
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Biochemistry, Biological sciences, Cell biology
- in
- iScience
- volume
- 28
- issue
- 8
- article number
- 113066
- publisher
- Elsevier
- external identifiers
-
- scopus:105010873053
- pmid:40734675
- ISSN
- 2589-0042
- DOI
- 10.1016/j.isci.2025.113066
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Author(s)
- id
- d275017a-11eb-49e1-884d-d6faf3a10cd0
- date added to LUP
- 2025-11-26 15:13:23
- date last changed
- 2025-11-27 03:00:03
@article{d275017a-11eb-49e1-884d-d6faf3a10cd0,
abstract = {{<p>Developing standardized bioengineered constructs that accurately replicate human skin is a largely sought-after goal. Pathways initiated at the nurturing interface with the dermal compartment have the potential to modulate the developing epidermal architecture. Here, we identified ascorbic acid, a dermis-donated metabolite, as key in modulating the phenotypical identity of immortalized keratinocytes. Priming monolayers with 2 μg/mL of the culture-stable derivative L-ascorbic acid 2-phosphate (A2P) led to the emergence of a basal-like phenotype within the cells, which showed increased clonogenicity, nuclear/cytoplasmic ratio, and upregulation of progenitor markers. Instead, surpassing this dose induced intracellular ascorbic acid accumulation and promoted a motile status. In organotypic cultures, pre-incubation of founding keratinocytes with 2 μg/mL of A2P improved epithelial layering, whereas higher pretreatments resulted in poor stratification. These findings suggest that ascorbic acid levels in the self-renewing epithelium have a fundamental role in determining whether cells initially commit to differentiation, ultimately influencing regenerative outcomes.</p>}},
author = {{Molina-Oviedo, Angie Katherine and Sorrentino, Ilaria and Clares-Pedrero, Irene and Salamanca-Gonzalez, Celina and Arevalo-Nuñez de Arenas, Eduardo and Mazariegos, Marina S. and Cabañas, Carlos and Medraño-Fernandez, Iria}},
issn = {{2589-0042}},
keywords = {{Biochemistry; Biological sciences; Cell biology}},
language = {{eng}},
month = {{08}},
number = {{8}},
publisher = {{Elsevier}},
series = {{iScience}},
title = {{Optimizing standardized lab-grown skin substitutes evidences a proliferation-differentiation switch based on ascorbic acid}},
url = {{http://dx.doi.org/10.1016/j.isci.2025.113066}},
doi = {{10.1016/j.isci.2025.113066}},
volume = {{28}},
year = {{2025}},
}