Controlling the Neuronal Differentiation of Stem Cells by the Intracellular Delivery of Retinoic Acid-Loaded Nanoparticles
Abstract
The manipulation of endogenous stem cell populations from the subventricular zone (SVZ), a neurogenic niche, creates an opportunity to induce neurogenesis and influence brain regenerative capacities in the adult brain. Herein, we demonstrate the ability of polyelectrolyte nanoparticles to induce neurogenesis exclusively after being internalized by SVZ stem cells. The nanoparticles are not cytotoxic for concentrations equal or below 10 μg/mL. The internalization process is rapid, and nanoparticles escape endosomal fate in a few hours. Retinoic acid-loaded nanoparticles increase the number of neuronal nuclear protein (NeuN)-positive neurons and functional neurons responding to depolarization with KCl and expressing NMDA receptor subunit type 1 (NR1). These nanoparticles offer an opportunity for in vivo delivery of proneurogenic factors and neurodegenerative disease treatment.
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Because of the hydrophobicity of RA, the occurrence of a burst release in most formulations is negligible.
“Because of the hydrophobicity of RA, the occurrence of a burst release in most formulations is negligible44,47,51,63.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
RA delivery systems have been prepared by complexation of RA with proteins or cationic polymers, by physical encapsulation in polymeric or inorganic nanoparticles, microparticles, micelles, liposomes, or films, by covalent attachment of RA to a carrier, or by immobilization of RA on surfaces of nanoparticles.
“Several strategies have been used to prepare RA delivery systems: namely, by complexation of RA with proteins (e.g., transthyretin)42 or cationic polymers (e.g., poly(ethyleneimine) (PEI))43,44, by physical encapsulation in polymeric25,44 or inorganic45 nanoparticles, microparticles46, micelles47,48, liposomes49, or films43, by covalent attachment of RA to a carrier50, or by immobilization of RA”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
In physical interaction, RA is complexed with positively charged polymers such as chitosan or PEI; the carboxylic acid of RA interacts electrostatically with the amine group located in the polymer, forming a complex that can be stabilized by addition of a polyanion and divalent ions.
“Regarding physical interaction, RA is complexed with positively charged polymers such as chitosan, or PEI43,51. The carboxylic acid of RA interacts electrostatically with the amine group located in the polymer, forming a complex that can be stabilized by addition of a polyanion and divalent ions43,44.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
The cellular uptake of some RA-containing nanoparticles has been demonstrated to take <12 h by clathrin-mediated endocytosis and macropinocytosis.
“The cellular uptake of some RA-containing nanoparticles has been demonstrated to take <12 h44 by clathrin-mediated endocytosis and macropinocytosis25.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
In vitro tests showed that ATRA-containing liposomes or ATRA-containing polymeric nanoparticles were 100-1000 times more active than soluble ATRA in cultured tumor cells or neural stem cells.
“In vitro tests showed that ATRA-containing liposomes69 or ATRA-containing polymeric nanoparticles25,44 were 100–1000 times more active than soluble ATRA in cultured tumor cells25,69 or neural stem cells (NSC)44.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
The effect was mediated by an increase in transcription of the pro-neurogenic genes Ngn1 and Mash1.
“The effect was mediated by an increase in transcription of the pro-neurogenic genes Ngn1 and Mash144,66.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
ATRA-containing nanoparticles have been developed to deliver RA into NSC niches.
“ATRA-containing nanoparticles have been also developed to deliver RA into NSC niches44.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
The nanoparticles had a higher effect on neuronal differentiation than solubilized RA both in vitro and in vivo.
“The nanoparticles had a higher effect on neuronal differentiation than solubilized RA both in vitro and in vivo44,66.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [44]
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- Authors
- Maia, J., Santos, T., Aday, S., Agasse, F., Cortes, L., Malva, J. O., Bernardino, L., & Ferreira, L.
- Affiliations
- University of Coimbra (PT)
- Neuroprotection and Neurogenesis in Brain Repair Group
- Biomaterials and Stem Cell-Based Therapeutics Group
- Microscopy and Flow Cytometry Unit
- Corresponding author
- Bernardino, Liliana
- Ferreira, Lino
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-12-20
- Volume
- 5
- Issue
- 1
- Pages
- 97-106
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2084116832
- Cited by
- 99
- References
- 45
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 3 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 11 · 2017: 10 · 2016: 6 · 2015: 8 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- retinoic acid, nanoparticles, neuronal differentiation, neurogenesis, polyelectrolyte nanoparticles, intracellular delivery, endosomal escape, NMDA receptor NR1, adult neurogenesis, neurodegenerative disease treatment, brain regeneration
- MeSH terms
- Animals, Biological Transport, Cell Differentiation, Cell Survival, Drug Carriers, Neurons, Stem Cells, Tretinoin, Intracellular Space, Cell Proliferation, Mice, Nanoparticles
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