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.

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

“…Importantly, differentiation was less evident when using higher concentrations of LR-NP in combination with laser treatment, indicating that RA-induced neurogenesis is dose dependent. This is in accordance with our previous studies where we reported that RA has an optimal concentration window to drive neuronal commitment of SVZ cells [37]. In contrast to neuronal differentiation results, there was no statistical significance between 60 sec of laser and LRNP+60s treatments regarding neuroblast proliferation (DCX+/Ki67+).…”

MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson's disease

“…In these conditions, SVZ cells grow in suspension and generate neurospheres that are rich in neural and progenitor stem cells at distinct stages of differentiation and with proliferative and selfrenewing abilities, as previously shown by us [7,24,[27][28][29][30]. Five to six-day-old neurospheres were seeded onto 0.1 mg/mL poly-D-lysine-(PDL; Sigma-Aldrich Co. Zeiss, Jena, Germany).…”

“…Viral vectors have a high capacity to deliver miR, however safety issues such as immunogenicity and the risk of triggering oncogenic transformation limits its translation potential [23]. Non-viral vectors such as polymeric nanoparticles (NPs), which avoid these safety issues, have been used by us and others to efficiently deliver proneurogenic molecules, including miR, into cells [7,[23][24][25]. As so, we hypothesized that the use of polymeric NPs to deliver miR-124 could promote neurogenesis of SVZ NSCs both in vitro and in vivo and ultimately promote brain repair.…”

Nanomedicine Approaches to Modulate Neural Stem Cells in Brain Repair

“…Importantly, functionalized nanostructured hydrogels were shown to successfully induce NSC differentiation while supporting tissue regeneration [6]. Recently, we have successfully developed a NP formulation capable of controlling NSC differentiation both in vitro and in vivo [3,4]. Contrary to soluble retinoic acid (RA), our results demonstrated that RA-NPs injected intracerebroventricularly contributed to the successful neuronal commitment of mouse subventricular zone (SVZ) NSCs.…”

“…Nanoparticulate systems for brain delivery (e.g., anticancer drugs, analgesics, antiAlzheimer's and anti-Parkinson's drugs) have been described in the past 25 years [2]. However, modulation of the activity/ differentiation of NSCs by nanoparticulate systems releasing small molecules was only recently demonstrated [3,4]. Current progress in the nanomedicine field has been stimulated by better understanding the biology of NSCs and by identifying molecular players capable of modulating their activity, proliferation, migration, and differentiation.…”