TY - JOUR
T1 - Remote Control of Intracellular Calcium Using Upconversion Nanotransducers Regulates Stem Cell Differentiation In Vivo
AU - Kang, Heemin
AU - Zhang, Kunyu
AU - Pan, Qi
AU - Lin, Sien
AU - Wong, Dexter Siu Hong
AU - Li, Jinming
AU - Lee, Wayne Yuk Wai
AU - Yang, Boguang
AU - Han, Fengxuan
AU - Li, Gang
AU - Li, Bin
AU - Bian, Liming
N1 - Funding Information:
H.K. and K.Z. contributed equally to this work. Projects 31570979 and 31530024 are supported by the National Natural Science Foundation of China. This work is supported by National Key R&D Program of China (2016YFC1100203). The work described in this paper is supported by a General Research Fund grant from the Research Grants Council of Hong Kong (project nos 14202215 and 14220716). This work is supported by the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (04152836). The work was partially supported by Hong Kong Research Grants Council Theme-based Research Scheme (Ref. T13-402/17-N). This research is supported by the Chow Yuk Ho Technology Centre for Innovative Medicine, The Chinese University of Hong Kong. The authors are grateful for technical support from Josie Lai, Samuel Wong, and Anny Cheung in the School of Biomedical Sciences, The Chinese University of Hong Kong. The authors also thank Prof. Feng Wang and Ms. Tianying Sun in the Department of Materials Science and Engineering, City University of Hong Kong, for the help with the photoluminescence characterization of the UCNTs. The work was partially supported by grants from Research Grants Council of the Hong Kong Special Administrative Region, China (project nos 14119115, 14160917, 9054014 N_CityU102/15, and T13-402/17-N); National Natural Science Foundation of China (81772404, 81430049, and 81772322); Hong Kong Innovation Technology Commission Funds (ITS/UIM-305). This study was also supported in part by SMART program, Lui Che Woo Institute of Innovative Medicine. The animal experiments in this work were approved by the Institutional Animal Care and Use Committee at the Chinese University of Hong Kong.
Publisher Copyright:
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/10/10
Y1 - 2018/10/10
N2 - Remote control of stem cell differentiation in vivo by stimuli-responsive nanomaterials with the use of tissue-penetrative stimuli is an appealing strategy for versatile regulation in stem cell therapy. In this study, an upconversion nanotransducer (UCNT)-based nanocomplex with photolabile caging of chondro-inductive kartogenin (KGN) and/or either calcium chelator or calcium supplier (caged calcium), and subsequent coupling of integrin-binding ligand via cyclodextrin-adamantine supramolecular complexation is utilized. Near-infrared (NIR)-to-ultraviolet light conversion by UCNT nanocomplex triggered intracellular photo-uncaging and release of cargo molecules, thereby allowing direct regulation of real-time intracellular calcium levels. While intracellular KGN delivery led to the differentiation of human mesenchymal stem cells (hMSCs) into hypertrophic chondrocytes, NIR-regulated intracellular calcium decrease and KGN delivery induced their differentiation into chondrocytes by inhibiting hypertrophy. Conversely, intracellular calcium increase and KGN delivery promoted the differentiation of hMSCs into osteoblasts via endochondral pathway. To the best of knowledge, this is the first demonstration of utilizing NIR-controllable nanomaterials for regulating stem cell differentiation by controlling intracellular calcium, both in vitro and in vivo. This versatile control can facilitate the translation of stem cells to remotely controlled treatment of diseases in composite tissues involving various cell types.
AB - Remote control of stem cell differentiation in vivo by stimuli-responsive nanomaterials with the use of tissue-penetrative stimuli is an appealing strategy for versatile regulation in stem cell therapy. In this study, an upconversion nanotransducer (UCNT)-based nanocomplex with photolabile caging of chondro-inductive kartogenin (KGN) and/or either calcium chelator or calcium supplier (caged calcium), and subsequent coupling of integrin-binding ligand via cyclodextrin-adamantine supramolecular complexation is utilized. Near-infrared (NIR)-to-ultraviolet light conversion by UCNT nanocomplex triggered intracellular photo-uncaging and release of cargo molecules, thereby allowing direct regulation of real-time intracellular calcium levels. While intracellular KGN delivery led to the differentiation of human mesenchymal stem cells (hMSCs) into hypertrophic chondrocytes, NIR-regulated intracellular calcium decrease and KGN delivery induced their differentiation into chondrocytes by inhibiting hypertrophy. Conversely, intracellular calcium increase and KGN delivery promoted the differentiation of hMSCs into osteoblasts via endochondral pathway. To the best of knowledge, this is the first demonstration of utilizing NIR-controllable nanomaterials for regulating stem cell differentiation by controlling intracellular calcium, both in vitro and in vivo. This versatile control can facilitate the translation of stem cells to remotely controlled treatment of diseases in composite tissues involving various cell types.
KW - in vivo stem cell differentiation
KW - intracellular calcium regulation
KW - photocaging
KW - upconversion nanotransducers
UR - http://www.scopus.com/inward/record.url?scp=85052819899&partnerID=8YFLogxK
U2 - 10.1002/adfm.201802642
DO - 10.1002/adfm.201802642
M3 - Article
AN - SCOPUS:85052819899
VL - 28
JO - Advanced Functional Materials
JF - Advanced Functional Materials
SN - 1616-301X
IS - 41
M1 - 1802642
ER -
