Human iPSC-derived mesenchymal stem cells encapsulated in PEGDA hydrogels mature into valve interstitial-like cells

• Type of Material: Article
• Authors: Aline L.Y. Nachlas, Emory University; Siyi Li, Emory University; Rajneesh Jha, Emory University; Monalisa Singh, Children's Healthcare Atlanta; Chunhui Xu, Emory University; Michael Davis, Emory University
• Language: English
• Date: 2018-04-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.actbio.2018.02.025
• Title of Journal or Parent Work: Acta Biomaterialia
• ISSN: 1742-7061
• Volume: 71
• Start Page: 235
• End Page: 246
• Grant/Funding Information: This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory+Children’s Pediatric Research Center; supported in part by the Emory Flow Cytometry Core and the Emory Comprehensive Glycomics Core, both part of the Emory Integrated Core Facilities (EICF) and are subsidized by the Emory University School of Medicine.; This work was supported by The Betkowski Family Research Fund;NSF Graduate Research Fellowship; American Heart Association Predoctoral Fellowship;NRSA NIH F31 Predoctoral fellowship; Alfred P. Sloan Foundation; Goizueta Foundation to A.L.Y.N; and the Petit Scholar Program to S.L.; Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.
• Keywords: PROGRESS; Engineering, Biomedical; Materials Science, Biomaterials; Induced pluripotent stem cells; Engineering; Tissue engineering heart valves; HEART-VALVE; Mesenchymal stem cells; SCAFFOLDS; Technology; Materials Science; SMOOTH-MUSCLE-CELLS; CHILDREN; FUTURE; Science & Technology; GROWTH; FIBROBLASTS; DISEASE; REPLACEMENT; PEG; Hydrogel
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Despite recent advances in tissue engineered heart valves (TEHV), a major challenge is identifying a cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. This study demonstrates that induced pluripotent stem cells (iPSC)-derived mesenchymal stem cells (iMSCs) can be derived from iPSCs using a feeder-free protocol and then further matured into VICs by encapsulation within 3D hydrogels. The differentiation efficiency was characterized using flow cytometry, immunohistochemistry staining, and trilineage differentiation. Using our feeder-free differentiation protocol, iMSCs were differentiated from iPSCs and had CD90 + , CD44 + , CD71 + , αSMA + , and CD45 − expression. Furthermore, iMSCs underwent trilineage differentiation when cultured in induction media for 21 days. iMSCs were then encapsulated in poly(ethylene glycol)diacrylate (PEGDA) hydrogels grafted with adhesion peptide (RGDS) to promote remodeling and further maturation into VIC-like cells. VIC phenotype was assessed by the expression of alpha-smooth muscle actin (αSMA), vimentin, and collagen production after 28 days. When MSC-derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, a decrease in αSMA expression and increase in vimentin was observed. In addition, iMSCs synthesized collagen type I after 28 days in 3D hydrogel culture. Thus, the results from this study suggest that iMSCs may be a promising cell source for TEHV. Statement of Significance: Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function.