Drug-loaded nanoparticles induce gene expression in human pluripotent stem cell derivatives.
Tissue engineering and advanced manufacturing of human stem cells requires a suite of tools to control gene expression spatiotemporally in culture. Inducible gene expression systems offer cell-extrinsic control, typically through addition of small molecules, but small molecule inducers typically contain few functional groups for further chemical modification. Doxycycline (DXC), a potent small molecule inducer of tetracycline (Tet) transgene systems, was conjugated to a hyperbranched dendritic polymer (Boltorn H40) and subsequently reacted with polyethylene glycol (PEG). The resulting PEG-H40-DXC nanoparticle exhibited pH-sensitive drug release behavior and successfully controlled gene expression in stem-cell-derived fibroblasts with a Tet-On system. While free DXC inhibited fibroblast proliferation and matrix metalloproteinase (MMP) activity, PEG-H40-DXC nanoparticles maintained higher fibroblast proliferation levels and MMP activity. The results demonstrate that the PEG-H40-DXC nanoparticle system provides an effective tool to controlling gene expression in human stem cell derivatives.
Department of Biomedical Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. sgong@engr.wisc.edu ksaha@wisc.edu.
Virendra
V
Gajbhiye
Leah
L
Escalante
Guojun
G
Chen
Alex
A
Laperle
Qifeng
Q
Zheng
Benjamin
B
Steyer
Shaoqin
S
Gong
Krishanu
K
Saha
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000737:chemistry* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
D004337:Drug Carriers; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin; D020782:Matrix Metalloproteinases