Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics.
Studies in hypertension (HTN) pharmacogenomics seek to identify genetic sources of variable antihypertensive drug response. Genetic association studies have detected single-nucleotide polymorphisms (SNPs) that link to drug responses; however, to understand mechanisms underlying how genetic traits alter drug responses, a biological interface is needed. Patient-derived induced pluripotent stem cells (iPSCs) provide a potential source for studying otherwise inaccessible tissues that may be important to antihypertensive drug response. The present study established multiple iPSC lines from an HTN pharmacogenomics cohort. We demonstrated that established HTN iPSCs can robustly and reproducibly differentiate into functional vascular smooth muscle cells (VSMCs), a cell type most relevant to vasculature tone control. Moreover, a sensitive traction force microscopy assay demonstrated that iPSC-derived VSMCs show a quantitative contractile response on physiological stimulus of endothelin-1. Furthermore, the inflammatory chemokine tumor necrosis factor α induced a typical VSMC response in iPSC-derived VSMCs. These studies pave the way for a large research initiative to decode biological significance of identified SNPs in hypertension pharmacogenomics.


CONCLUSIONS
Treatment of hypertension remains suboptimal, and a pharmacogenomics approach seeks to identify genetic biomarkers that could be used to guide treatment decisions; however, it is important to understand the biological underpinnings of genetic associations. Mouse models do not accurately recapitulate individual patient responses based on their genetics, and hypertension-relevant cells are difficult to obtain from patients. Induced pluripotent stem cell (iPSC) technology provides a great interface to bring patient cells with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective and reproducible method of generating functional vascular smooth muscle cells.
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA Center for Cellular Reprogramming, University of Florida, Gainesville, Florida, USA.
Nikolett M
NM
Biel
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA Center for Cellular Reprogramming, University of Florida, Gainesville, Florida, USA.
Katherine E
KE
Santostefano
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA Center for Cellular Reprogramming, University of Florida, Gainesville, Florida, USA.
Bayli B
BB
DiVita
Department of Pharmacotherapy and Translational Research, College of Pharmacy and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.
Nihal
N
El Rouby
J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, Florida, USA.
Santiago D
SD
Carrasquilla
Mechanical and Aerospace Engineering, College of Engineering, University of Florida, Gainesville, Florida, USA Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Chelsey
C
Simmons
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.
Mahito
M
Nakanishi
Department of Pharmacotherapy and Translational Research, College of Pharmacy and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Rhonda M
RM
Cooper-DeHoff
Department of Pharmacotherapy and Translational Research, College of Pharmacy and Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Julie A
JA
Johnson
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA Center for Cellular Reprogramming, University of Florida, Gainesville, Florida, USA Nikolett.Biel@otsuka-us.com terada@pathology.ufl.edu.
Naohiro
N
Terada
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology
Hypertension; Induced pluripotent stem cells; Personalized medicine; Vascular smooth muscle cells