Engineering innervated secretory epithelial organoids by magnetic three-dimensional bioprinting for stimulating epithelial growth in salivary glands

被引:102
作者
Adine, Christabella [1 ]
Ng, Kiaw K. [1 ]
Rungarunlert, Sasitorn [2 ]
Souza, Glauco R. [3 ,4 ]
Ferreira, Joao N. [1 ,5 ,6 ]
机构
[1] Natl Univ Singapore, Fac Dent, Singapore, Singapore
[2] Mahidol Univ, Fac Vet Sci, Dept Preclin & Appl Anim Sci, Salaya 73170, Nakhon Pathom, Thailand
[3] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA
[4] Nano3D Biosci Inc, Houston, TX USA
[5] Chulalongkorn Univ, Fac Dent, 54 Henri Dunant Rd, Bangkok 10330, Thailand
[6] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA
基金
英国医学研究理事会;
关键词
Bioprinting; Magnetic nanoparticles; Organoids; Salivary gland; Radiotherapy; Xerostomia; STEM-CELLS; MODELING DEVELOPMENT; EXPRESSION; THERAPY; MORPHOGENESIS; HYPOFUNCTION; ORGANIZATION; SCAFFOLDS; RADIATION; HYDROGELS;
D O I
10.1016/j.biomaterials.2018.06.011
中图分类号
R318 [生物医学工程];
学科分类号
100103 [病原生物学];
摘要
Current saliva-based stimulation therapies for radiotherapy-induced xerostomia are not fully effective due to the presence of damaged secretory epithelia and nerves in the salivary gland (SG). Hence, three-dimensional bio-engineered organoids are essential to regenerate the damaged SG. Herein, a recently validated three-dimensional (3D) biofabrication system, the magnetic 3D bio-printing (M3DB), is tested to generate innervated secretory epithelial organoids from a neural crest derived mesenchymal stem cell, the human dental pulp stem cell (hDPSC). Cells are tagged with magnetic nanoparticles (MNP) and spatially arranged with magnet dots to generate 3D spheroids. Next, a SG epithelial differentiation stage was completed with fibroblast growth factor 10 (4-400 ng/ml) to recapitulate SG epithelial morphogenesis and neurogenesis. The SG organoids were then transplanted into ex vivo model to evaluate their epithelial growth and innervation. M3DB-formed spheroids exhibited both high cell viability rate (>90%) and stable ATP intracellular activity compared to MNP-free spheroids. After differentiation, spheroids expressed SG epithelial compartments including secretory epithelial, ductal, myoepithelial, and neuronal. Fabricated organoids also produced salivary alpha-amylase upon FGF10 stimulation, and intracellular calcium mobilization and trans epithelial resistance was elicited upon neurostimulation with different neurotransmitters. After transplantation, the SG-like organoids significantly stimulated epithelial and neuronal growth in damaged SG. It is the first time bio-functional innervated SG-like organoids are bioprinted. Thus, this is an important step towards SG regeneration and the treatment of radiotherapy-induced xerostomia. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码:52 / 66
页数:15
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