Cardiac differentiation of cardiosphere-derived cells in scaffolds mimicking morphology of the cardiac extracellular matrix.
Stem cell therapy has the potential to regenerate heart tissue after myocardial infarction (MI). The regeneration is dependent upon cardiac differentiation of the delivered stem cells. We hypothesized that timing of the stem cell delivery determines the extent of cardiac differentiation as cell differentiation is dependent on matrix properties such as biomechanics, structure and morphology, and these properties in cardiac extracellular matrix (ECM) continuously vary with time after MI. In order to elucidate the relationship between ECM properties and cardiac differentiation, we created an in vitro model based on ECM-mimicking fibers and a type of cardiac progenitor cell, cardiosphere-derived cells (CDCs). A simultaneous fiber electrospinning and cell electrospraying technique was utilized to fabricate constructs. By blending a highly soft hydrogel with a relatively stiff polyurethane and modulating fabrication parameters, tissue constructs with similar cell adhesion property but different global modulus, single fiber modulus, fiber density and fiber alignment were achieved. The CDCs remained alive within the constructs during a 1week culture period. CDC cardiac differentiation was dependent on the scaffold modulus, fiber volume fraction and fiber alignment. Two constructs with relatively low scaffold modulus, ∼50-60kPa, most significantly directed the CDC differentiation into mature cardiomyocytes as evidenced by gene expressions of cardiac troponin T (cTnT), calcium channel (CACNA1c) and cardiac myosin heavy chain (MYH6), and protein expressions of cardiac troponin I (cTnI) and connexin 43 (CX43). Of these two low-modulus constructs, the extent of differentiation was greater for lower fiber alignment and higher fiber volume fraction. These results suggest that cardiac ECM properties may have an effect on cardiac differentiation of delivered stem cells.
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Yanyi
Y
Xu
Department of Agricultural & Biological Engineering, Mississippi State University, Starkville, MS 39672, USA.
Sourav
S
Patnaik
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Xiaolei
X
Guo
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Zhenqing
Z
Li
Department of Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Wilson
W
Lo
Department of Clinical Science, Mississippi State University, Starkville, MS 39672, USA.
Ryan
R
Butler
Department of Clinical Science, Mississippi State University, Starkville, MS 39672, USA.
Andrew
A
Claude
Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Zhenguo
Z
Liu
Department of Biomedical Engineering, University of Akron, Akron, OH 44325, USA.
Ge
G
Zhang
Department of Agricultural & Biological Engineering, Mississippi State University, Starkville, MS 39672, USA.
Jun
J
Liao
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Peter M
PM
Anderson
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA. Electronic address: guan.21@osu.edu.
Jianjun
J
Guan
D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D018874:Spheroids, Cellular / Q000166:cytology / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D023822:Tissue Engineering / Q000379:methods
D020100:Hydrogels
Cardiac differentiation; Cardiosphere-derived cells; Matrix modulus; Stem cell therapy