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Photothermal Modulation of Human Stem Cells Using Light-Responsive 2D Nanomaterials

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Photothermal Modulation of Human Stem Cells Using Light-Responsive 2D Nanomaterials Photothermal modulation of human stem cells using light-responsive 2D nanomaterials James K. Carrowa,1, Kanwar Abhay Singha,1, Manish K. Jaiswala, Adelina Ramireza, Giriraj Lokhandea, Alvin T. Yeha, Tapasree Roy Sarkarb, Irtisha Singha,c,2, and Akhilesh K. Gaharwara,d,e,2 aBiomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843; bDepartment of Biology, Texas A&M University, College Station, TX 77843; cDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center, Texas A&M University, Bryan, TX 77807; dMaterials Science and Engineering, College of Engineering, Texas A&M University, College Station, TX 77843; and eCenter for Remote Health Technologies and Systems, Texas A&M University, College Station, TX 77843 Edited by Catherine J. Murphy, University of Illinois at Urbana–Champaign, Urbana, IL, and approved April 10, 2020 (received for review August 18, 2019) Two-dimensional (2D) molybdenum disulfide (MoS2) nanomateri- Subsequently, we utilize RNA-seq to characterize the in-depth and als are an emerging class of biomaterials that are photoresponsive unbiased effect of MoS2 on the gene expression program of hMSCs. at near-infrared wavelengths (NIR). Here, we demonstrate the RNA-seq reveals the steady-state expression of the transcriptome ability of 2D MoS to modulate cellular functions of human stem 2 after the MoS2 treatment, as well as the photothermal effect of cells through photothermal mechanisms. The interaction of MoS2 MoS2 at near-infrared wavelengths (NIR). This information assists and NIR stimulation of MoS2 with human stem cells is investigated in identifying the role of MoS and NIR exposure in influencing key using whole-transcriptome sequencing (RNA-seq). Global gene ex- 2 signaling pathways. pression profile of stem cells reveals significant influence of MoS2 and NIR stimulation of MoS2 on integrins, cellular migration, and Biophysical Characterization of MoS2 Nanosheets wound healing. The combination of MoS and NIR light may pro- 2 Bulk MoS is composed of atomically thin S–Mo–S sheets vide new approaches to regulate and direct these cellular func- 2 tions for the purposes of regenerative medicine as well as stacked by short-range van der Waals forces. Bulk MoS2 was cancer therapy. chemically exfoliated following previously reported protocols (3, 18, 19). X-ray diffraction (XRD) of bulk MoS2 showed charac- two-dimensional (2D) nanomaterials | whole-transcriptome sequencing | teristic peaks at (002), (004), (103), (006), (105), and (008), while ENGINEERING cell–nanoparticles interactions | human mesenchymal stem cells | cell peaks broadened postexfoliation at (002), (100), and (110) as adhesion indexed by Joint Committee on Powder Diffraction File card number 37-1492 (Fig. 1A). The peaks of exfoliated MoS2 in- wo-dimensional (2D) nanomaterials are an emerging class of dicated a hexagonal structure. Using Bragg’s equation [2d sin(θ) Tmaterials with anisotropic layered structure that have shown = nλ], the interlayer spacing [(002) Miller indices spacing] of – distinct physical and chemical properties (1 4). Recently, 2D exfoliated MoS2 is 6.328 Å, which is larger than the interlayer transition metal dichalcogenides (TMDs) such as molybdenum spacing of bulk MoS2 (6.124 Å). The full width at half maximum disulfide (MoS2) have been explored for biomedical applications of peak (002) was 0.089 rad for bulk MoS2, which increased to due to their photothermal characteristics (5–9). Specifically, the 2.493 rad for exfoliated MoS2. The crystallite sizes for bulk and generation of ultrathin sheets via exfoliation of MoS2 enables the formation of direct bandgap nanosheets, which can be utilized Significance for light-based therapies (8, 10–13). In addition, the absence of dangling bonds from terminal sulfur atoms of MoS nano- 2 We demonstrate the ability of two-dimensional transition materials render high physiological stability (6, 10). The photo- metal dichalcogenides (TMDs) such as molybdenum disulfide responsive ability of 2D MoS along with its chemical stability in 2 (MoS ) to modulate and direct cellular functions of human stem biological microenvironments can be exploited for the photo- 2 cells through photothermal modulation. The global gene ex- modulation of cellular functions. Although some studies have – pression profile of stem cells reveals significant influence on investigated cellular compatibility of 2D MoS2 (14 17), no integrins, cellular migration, and wound healing by photo- studies have explored their photomodulation ability. thermal modulation of MoS2. The photostimulation of MoS2 Understanding cellular responses following treatment with 2D may provide new approaches to regulate cellular migration MoS2, with and without photostimulation, will assist in exploring and related functions. their biomedical applications. Although molecular biology tech- niques such as PCR and microarrays can be used to evaluate the Author contributions: J.K.C., K.A.S., I.S., and A.K.G. designed research; J.K.C., K.A.S., effect of this treatment on cells, they are limited in throughput. To M.K.J., A.R., G.L., and I.S. performed research; A.K.G. contributed new reagents/analytic overcome this limitation, “omics” techniques can provide global tools; J.K.C., K.A.S., G.L., A.T.Y., T.R.S., I.S., and A.K.G. analyzed data; and J.K.C., K.A.S., I.S., high-throughput readouts of various cellular and molecular pro- and A.K.G. wrote the paper. cesses and can help discern affected cell–nanomaterials interac- The authors declare no competing interest. tions. Specifically, whole-transcriptome sequencing (RNA-seq) of This article is a PNAS Direct Submission. treated cells can provide an unbiased and global perspective of This open access article is distributed under Creative Commons Attribution-NonCommercial- stimulated cellular and molecular activity as well as pivotal sig- NoDerivatives License 4.0 (CC BY-NC-ND). Data deposition:The data reported in this paper have been deposited in the Gene Ex- naling pathways triggered by exposure to the nanomaterial. RNA- pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. seq can be used for determination and quantification of all GSE141456). expressed transcripts in cells by overcoming the limitations and 1J.K.C. and K.A.S contributed equally to this work. biases of conventional PCR and microarrays analysis. 2To whom correspondence may be addressed. Email: [email protected] or isingh@ Here, we report interactions of exfoliated MoS2 with human tamu.edu. mesenchymal stem cells (hMSCs) by uncovering molecular targets This article contains supporting information online at https://www.pnas.org/lookup/suppl/ and affected signaling pathways. We first examine the interplay doi:10.1073/pnas.1914345117/-/DCSupplemental. of 2D MoS2 with biomolecules under physiological conditions. First published May 27, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1914345117 PNAS | June 16, 2020 | vol. 117 | no. 24 | 13329–13338 Downloaded by guest on October 3, 2021 Exfoliated Molybdenum Disulfide (MoS ) A Bulk Molybdenum Disulfide (MoS2) 2 Exfoliated MoS Bulk MoS2 2 (002) (002) (100) (110) (004) (006) (008) Intensity (a.u) Intensity (a.u) (103) (105) 10 20 30 40 50 60 70 10 20 30 40 50 60 70 2 (degrees) 2 (degrees) B C 4 200 110 3 2 105 2 103 1 1 100 Height (nm) 3 0 5 m 1 m 10 nm-1 -1 100 nm 0123 Distance (μm) D E F G Bulk Bulk ).u.a( Atomic ( %) Mo 3d Bulk Bulk 5/2 Exfoliated Exfoliated Exfoliated S 2p3/2 Exfoliated Sample Mo S A1g Mo 3d ).u yti Bulk 14.8 % 85.2 % .a sne (ytisne t Exfoliated 22.8 % 77.2 % n S 2p Idezilam 1/2 E1 E 2g tn 1g Intensity (a.u.) I J r Raman Intensity (a.u.) 3 oN J2 226 230 234 160 162 164 200 300 400 500 600 650 700 750 800 Binding energy (eV) Binding energy (eV) Raman Shift (cm-1) Wavelengh (nm) H Photo-thermal stimulation via near infrared (NIR) (λ = 800 nm, 28 Control (water) P = 340 mW/cm2, t = 7 mins) Control (media) Control (no MoS )MMoS (500 g/mL) oS(2 mg/mL) 26 2 2 mg/mL MoS2 (340 mW/cm ) 2 2 mg/mL MoS2 (20 mW/cm ) 24 2 500 g/mL MoS2 (340 mW/cm ) 2 500 g/mL MoS2 (20 mW/cm ) Temperature (°C) Temperature 22 15 mm Thermal Imaging 01234567891011 Time (min) IJ 0 800 40000 * Protein + SDS (-control) * Protein only (+control) -10 600 30000 Protein + 50 g/ml MoS2 Protein + 100 g/ml MoS * 2 Protein + 150 g/ml MoS 20000 2 -20 400 MoS only * 2 -30 200 Intensity (a.u.) PL Zeta Potential (mV) 10000 Hydrodynamic diameter (nm) -40 0 0 400 450 500 550 600 400 450 500 550 600 ater PBS PBS W Media Water Media Wavelength (nm) Wavelength (nm) Fig. 1. Physicochemical characterization of exfoliate 2D MoS2 nanosheets. (A) XRD of bulk and exfoliated MoS2.(B) AFM measures micrometer-sized nanosheets with nanometer thickness, confirming 2D shape. (C) TEM images of ultrathin MoS2 sheets displayed overlapping layers; each individual layer is numbered. Further, electron diffraction corroborated the formation of the 1T phase following lithium intercalation. (D) Atomic composition of bulk and exfoliated MoS2 determined via elemental analysis. (E) Crystallographic transformations from bulk to exfoliated MoS2 were monitored with XPS analysis with shifts from 2H to 1T phases observed. (F) Raman spectroscopy and (G) photoluminescent measurements likewise indicated structural modifications had occurred, seen through changes in vibrational energy bands and luminescent intensity, respectively. (H) Response to NIR light was determined using an IR camera and change in temperature over time. (I) Zeta potential and hydrodynamic size of exfoliated MoS2 in water, PBS, and media. (J) ANS assay shows protein structures are intact in the presence of exfoliated MoS2. 13330 | www.pnas.org/cgi/doi/10.1073/pnas.1914345117 Carrow et al. Downloaded by guest on October 3, 2021 exfoliated MoS2 were calculated using Scherrer equation as the interface of bound charges and diffuse layer, is shifted further ∼120 nm and 3.5 nm, respectively.
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