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Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells

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Abstract

Neurodevelopmental processes of pluripotent cells, such as proliferation and differentiation, are influenced by external natural forces. Despite the presence of biogenic magnetite nanoparticles in the central nervous system and constant exposure to the Earth’s magnetic fields and other sources, there is scant knowledge regarding the role of electromagnetic stimuli in neurogenesis. Moreover, emerging applications of electrical and magnetic stimulation to treat neurological disorders emphasize the relevance of understanding the impact and mechanisms behind these stimuli. Here, the effects of magnetic nanoparticles (MNPs) in polymeric coatings and the static external magnetic field (EMF) were investigated on neural induction of murine embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs). The results show that the presence of 0.5% MNPs in collagen-based coatings facilitates the migration and neuronal maturation of mESCs and hiPSCs in vitro. Furthermore, the application of 0.4 Tesla EMF perpendicularly to the cell culture plane, discernibly stimulates proliferation and guide fate decisions of the pluripotent stem cells, depending on the origin of stem cells and their developmental stage. Mechanistic analysis reveals that modulation of ionic homeostasis and the expression of proteins involved in cytostructural, liposomal and cell cycle checkpoint functions provide a principal underpinning for the impact of electromagnetic stimuli on neural lineage specification and proliferation. These findings not only explore the potential of the magnetic stimuli as neural differentiation and function modulator but also highlight the risks that immoderate magnetic stimulation may affect more susceptible neurons, such as dopaminergic neurons.

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Acknowledgments

HU acknowledges grant support by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, proj. No. 2018/07366-4). DFSP acknowledges grant support by FAPESP (2018/134942-2). ATS is grateful for a doctorate fellowship granted by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, proj. No. 163310/2014-9). LVP acknowledges grant support FAPESP/CEPID 2013/08135-2. FTA is grateful for a doctorate fellowship granted by FAPESP (2014/25487-3), Conselho Nacional de Desenvolvimento Científico e Tecnológico Departamento de Ciência e Tecnologia do Ministério da Saúde (Neurodegenerative Diseases Study - chamada CNPq/MS/DECIT- 24/2014), Banco Nacional de Desenvolvimento Economico e Social (BNDES), Fundação de Apoio à Universidade de São Paulo (FUSP – project 2358) and Sanofi Genzyme Coorporation (Gaucher Generation 2010 grant program - GZ-2011-10731). MFRF acknowledges grant support by FAPESP (project No. 2013/08028-1; 2018/07592-4). RRC received a scholarship from FAPESP (project No. 2016/14513-8). JC-V was funded by a postdoctoral fellowship of the INCT-REGENERA (National Institute of Science and Technology in Regenerative Medicine). APJS is grateful for a doctorate fellowship and an exchange doctorate fellowship financed by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES, proj. No. 88882.332985/2018-01 and 8881.186506/2018-01). ÁO-G is grateful for a postdoctoral fellowship granted by FAPESP (2019/26852-0). Y.D.T. acknowledges funding by The US AMRMC (W81XWH-15-1-0621), The SCI Trust Fund of The Commonwealth of Massachusetts, The Gordon Project to Cure Clinical Paralysis, The Cele H. and William B. Rubin Family Fund, and The Roosevelt Warm Springs Foundation. The authors thank Prof. Daniel R. Cornejo, Institute of Physics, University of São Paulo, for the magnetization measurements. The graphical abstract and Fig. 1 were created using Biorender.com.

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Data are available on request from Dr. Ana T. Semeano, Prof. Denise F.S. Petri and Prof. Henning Ulrich.

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748. Sala 964 Bloco 9 Superior, Cidade Universitária, São Paulo, SP, 05508-000, Brazil

    Ana T. Semeano, Juliana C. Corrêa-Velloso, Ana P. de Jesus Santos, Ágatha Oliveira-Giacomelli & Henning Ulrich

  2. Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748. Sala 307 Bloco 3 Inferior, Cidade Universitária, São Paulo, SP, 05508-000, Brazil

    Ana T. Semeano & Denise F. S. Petri

  3. Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, 02115, USA

    Ana T. Semeano

  4. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil

    Fabiano A. Tofoli, Rafaela R. Cardoso, Gustavo Ribeiro, Merari F. R. Ferrari & Lygia V. Pereira

  5. Department of Microbiology, Immunology and Parasitology at Federal University of Santa Catarina, Florianópolis, Brazil

    Mateus A. Pessoa & Edroaldo Lummertz da Rocha

  6. Laboratory of SCI, Stem Cell and Recovery Neurobiology Research, Department of Physical Medicine & Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital Network, and Mass General Brigham, Boston, MA, USA

    Yang D. Teng

Authors
  1. Ana T. Semeano
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  2. Fabiano A. Tofoli
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  3. Juliana C. Corrêa-Velloso
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  4. Ana P. de Jesus Santos
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  5. Ágatha Oliveira-Giacomelli
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  6. Rafaela R. Cardoso
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  7. Mateus A. Pessoa
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  8. Edroaldo Lummertz da Rocha
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  9. Gustavo Ribeiro
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  10. Merari F. R. Ferrari
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  11. Lygia V. Pereira
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  12. Yang D. Teng
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  13. Denise F. S. Petri
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  14. Henning Ulrich
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Contributions

ATSS, FTA, HU and DFSP conceived conceptual ideas; ATSS, FTA JC-V, APJS and RRC performed the experiments and data interpretation; ÁO-G, MAP, MFRF, ELR and GR performed data analysis; ATSS wrote the manuscript under supervision of HU and DSP; HU, DFSP, YDT, LVP, FTA, ÁO-G and MFRF made suggestions on manuscript, revised and edited the manuscript; HU, DFSP and LVP obtained financing of the project and supervised the experimental work.

Corresponding authors

Correspondence to Denise F. S. Petri or Henning Ulrich.

Ethics declarations

Ethics’ Approval

The project was submitted to the Ethics Committee in Research of the University of Sao Paulo (USP-CEP) and approved for human research (Protocol: 112/2010) and for experiments with animals (Protocol: 116/2010). It was also approved by the Departmental Board of the Genetics Department and Evolutionary Biology of Biosciences Institute (BI) - USP (Order N°: 354–2011, Meeting: 399, Item N°: 3.2, Date: 02.03.2011; by the Ethics Committee for Analysis of Research Projects (CAPPesq) of the Hospital das Clínicas (N° 0754/11) by CEP Hemorio (Project No. 251/11,Date:03/15/2011); and by the Brazilian National Committee of Ethics in Research (CONEP) - 071/2013, registry n° 16.899, process No. 25000.069088–2012-57.

Consent for Publication

This manuscript has been approved by all authors and is solely the work of the authors named.

Conflict of Interest

H.U. obtains consulting fees from TissueGnostics, Vienna, Austria. This did not influence data acquisition and analysis and drawn conclusions. The other authors declare that they have no known competing financial interests or personal relationships that influence the work reported in this paper.

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This article belongs to the Topical Collection: Special Issue on Neurogenesis and Neurodegeneration: Basic Research and Clinic Applications

Guest Editor: Henning Ulrich

Supplementary Information

Table S1

Final concentrations of the reagents used to supplement dopaminergic neural differentiation medium (PNG 69 kb)

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Table S2

Sequences of primers used in real-time PCR assays (PNG 65 kb)

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Table S3

Primary antibodies used in immunocytochemistry (CI) and flow cytometry (CF) assays (PNG 63 kb)

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Table S4

Secondary antibodies used in immunocytochemistry (CI) and flow cytometry (CF) assays (PNG 38 kb)

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Table S5

Complementary characteristics of hiPSCs samples. The study was performed with 3 samples of peripheral blood mononuclear cells (PBMNC) collected and reprogrammed into iPSC (PNG 25 kb)

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Fig. S1

Chronological representation of the culture and neuronal differentiation of embryonic stem cells. E14TG2a mouse embryonic stem cells (ESCs) were maintained in a pluripotency stage due to the presence of leukemia inhibitory factor (LIF) during (Step 0). After at least two passages in this stage, we proceeded to Step 1 with the formation of EBs in non-adherent culture for 2 days, followed by the induction of neural differentiation with retinoic acid (RA) for another 4 days. On the 6th day of differentiation, Step 2 begins. In this step 2, embryoid bodies (EBs) were seeded onto adherent polymeric substrates, promoting cell migration for 2 days, and neuronal differentiation was induced by culture medium supplementation with basic fibroblast growth factor (bFGF) and N-2 for another 12 days, with exchanging for fresh medium every 2 days. The representative images of each stage, presented in (A), (B) and (C) show, respectively, the colonies of undifferentiated ESCs (400μm calibration bar), suspended EBs (1050 μm calibration bar) and cell migration and differentiation from the adhered EBs (400 μm calibration bar) (PNG 274 kb)

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Fig. S2

Chronological representation of the culture and dopaminergic neuronal differentiation. Undifferentiated human induced pluripotent stem cells (iPSCs) were grown in E8 medium until reaching 90% confluence, proceeding with daily medium refreshment containing 1x penicillin/ streptomycin antibiotics and 1x Glutamax and additionally supplemented with the factors schematically detailed in this timeline: cAMP: cyclic adenosine monophosphate; AA: Ascorbic Acid (vitamin C); BDNF: brain derived neurotrophic factor, CHIR: CHIR99021: DAPT: γ-secretase inhibitor; FGF-8: fibroblast growth factor 8; GDNF: glial cell-line derived neurotrophic factor; LDN: LDN193189; Pur.: purmorphamine; SB: SB431542; SHH: sonic hedgehog; TGFβ3: transforming growth factor beta 3. Respective concentrations dare detailed in Table S1. On day 20 of differentiation (DIV 20), cell passages of 2x105 cells/ well are performed into 12-well plates previously treated with 2x Geltrex coating. The cells were grown at 37 °C in KnockOut™ Serum Replacement (KRS) medium in a controlled atmosphere of 5% CO2 and 95% humidity. Representative images taken on DIV 2 ((A), 1,000 μm scale bar), DIV 20 ((B), 400 μm scale bar) and DIV 36 ((C), 400 μm scale bar) (PNG 407 kb)

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Fig. S3

Influence of the polymeric substrate and the presence of MNPs on adhesion of EBs. EBs were seeded on gelatin, poly-L-lysine, xanthan and polymer blend CPAM: xanthan (1: 10) coating matrices, with and without 1 wt% MNPs in the polymeric substrate composition. Cell adhesion was quantified by the percentage of adhered EBs. Data are reported as mean values ± SD; * p < 0.05 and ** p < 0.001 for culture on substrates in the presence of MNPs compared to culture on their substrates in the absence of MNPs (control) (PNG 89 kb)

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Fig. S4

Alignment of MNPs surrounding EBs and accumulating along neural processes. The red and white arrows show the orientation of MNPs along neural elongations and EBs, respectively (PNG 380 kb)

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Fig. S5

Morphology of cell culture stimulated with EMF (N/S) during Stage I, Stage II or both (I=II). Scale bar 60 μm (PNG 297 kb)

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Fig. S6

Illustrative images of cells labeled with LysoSensor blue-yellow. Acidic vesicles were labeled in yellow, and less acidic vesicles were blue. A-C control cells; D-E cells under EMF (PNG 148 kb)

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Semeano, A.T., Tofoli, F.A., Corrêa-Velloso, J.C. et al. Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells. Stem Cell Rev and Rep 18, 1337–1354 (2022). https://doi.org/10.1007/s12015-022-10332-0

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