title: Cell number per spheroid and electrical conductivity of nanowires influence the function of silicon nanowired human cardiac spheroids.
abstract: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an unlimited cell source to treat cardiovascular diseases, the leading cause of death worldwide. However, current hiPSC-CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e-SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. Here, we examined two important factors that can affect functions of the nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. To examine the first factor, we prepared hiPSC cardiac spheroids with four different sizes by varying cell number per spheroid (∼0.5k, ∼1k, ∼3k, ∼7k cells/spheroid). Spheroids with ∼3k cells/spheroid was found to maximize the beneficial effects of the 3D spheroid microenvironment. This result was explained with a semi-quantitative theory that considers two competing factors: 1) the improved 3D cell-cell adhesion, and 2) the reduced oxygen supply to the center of spheroids with the increase of cell number. Also, the critical role of electrical conductivity of silicon nanowires has been confirmed in improving tissue function of hiPSC cardiac spheroids. These results lay down a solid foundation to develop suitable nanowired hiPSC cardiac spheroids as an innovative cell delivery system to treat cardiovascular diseases.
  
  
  
  Cardiovascular disease is the leading cause of death and disability worldwide. Due to the limited regenerative capacity of adult human hearts, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have received significant attention because they provide a patient specific cell source to regenerate damaged hearts. Despite the progress, current human hiPSC-CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e-SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. In this manuscript, we examined the effects of two important factors on the functions of nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. The results from these studies will allow for the development of suitable nanowired hiPSC cardiac spheroids to effectively deliver hiPSC-CMs for heart repair.
authors.affiliation: Bioengineering Department, Clemson University, Clemson, SC 29634, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Bioengineering Department, Clemson University, Clemson, SC 29634, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Richards
authors.affiliation: Bioengineering Department, Clemson University, Clemson, SC 29634, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Coyle
authors.affiliation: Academic Magnet High School, North Charleston, SC 29405, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Chemistry, The James Franck Institute and the Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Gou
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, Gazes Cardiac Research Institute, Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Menick
authors.affiliation: Department of Chemistry, The James Franck Institute and the Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Bozhi
authors.initials: B
authors.lastname: Tian
authors.affiliation: Bioengineering Department, Clemson University, Clemson, SC 29634, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mei@clemson.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mei
mesh_terms: D002452:Cell Count; D048429:Cell Size; D004553:Electric Conductivity; D005455:Fluorescent Antibody Technique; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology*; D053770:Nanowires / Q000737:chemistry* / Q000648:ultrastructure; D012825:Silicon / Q000737:chemistry*; D018874:Spheroids, Cellular / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D012825:Silicon
keywords: Human induced pluripotent stem cell-derived cardiomyocytes; Oxygen transport; Silicon nanowires; Spheroids