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Microfibrous Scaffolds Enhance Endothelial Differentiation and Organization of Induced Pluripotent Stem Cells

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Abstract

Introduction

Human induced pluripotent stem cells (iPSCs) are a promising source of endothelial cells (iPSC-ECs) for engineering three-dimensional (3D) vascularized cardiac tissues. To mimic cardiac microvasculature, in which capillaries are oriented in parallel, we hypothesized that endothelial differentiation of iPSCs within topographically aligned 3D scaffolds would be a facile one-step approach to generate iPSC-ECs as well as induce aligned vascular organization.

Methods

Human iPSCs underwent endothelial differentiation within electrospun 3D polycaprolactone (PCL) scaffolds having either randomly oriented or parallel-aligned microfibers. Using gene, protein, and endothelial functional assays, endothelial differentiation was compared between conventional two-dimensional (2D) films and 3D scaffolds having either randomly oriented or aligned microfibers. Furthermore, the role of parallel-aligned microfiber patterning on the organization of vessel-like networks was assessed.

Results

The cells in both the randomly oriented and aligned 3D scaffolds demonstrated an 11-fold upregulation in gene expression of the endothelial phenotypic marker, CD31, compared to cells on 2D films. This upregulation corresponded to >3-fold increase in CD31 protein expression in 3D scaffolds, compared to 2D films. Concomitantly, other endothelial phenotypic markers including CD144 and endothelial nitric oxide synthase also showed significant transcriptional upregulation in 3D scaffolds by >7-fold, compared to 2D films. Nitric oxide production, which is characteristic of endothelial function, was produced 4-fold more abundantly in 3D scaffolds, compared to on 2D PCL films. Within aligned scaffolds, the iPSC-ECs displayed parallel-aligned vascular-like networks with 70% longer branch length, compared to cells in randomly oriented scaffolds, suggesting that fiber topography modulates vascular network-like formation and patterning.

Conclusion

Together, these results demonstrate that a 3D scaffold structure promotes endothelial differentiation, compared to 2D substrates, and that aligned topographical patterning induces anisotropic vascular network-like organization.

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Acknowledgments

We thank Joshua Knowles, MD, Ph.D. and Ivan Carcamo-Orive, Ph.D., for technical assistance in endothelial differentiation. This study was supported by grants to NFH from the US National Institutes of Health (R00HL098688, R01HL127113, and R21EB020235), Merit Review Award (1I01BX002310) from the Department of Veterans Affairs Biomedical Laboratory Research and Development, the Stanford Women and Sex Differences in Medicine Center, the Stanford Child Health Research Institute. NFH was also supported by a McCormick Gabilan fellowship. MW was supported by a diversity supplement through the US National Institutes of Health (R01HL127113). In addition, this study was supported in part by a grant from US National Institutes of Health (NCATS-CTSA, UL1 TR001085). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.

Conflict of interest

The authors (Joseph J. Kim, Luqia Hou, Guang Yang, Nicholas P. Mezak, Maureen Wanjare, Lydia M. Joubert, and Ngan F. Huang) declare that they have no conflicts of interest.

Ethical Approval

All human subjects research were carried out with informed consent in accordance with institutional guidelines and approved by the Institutional Review Board at Stanford University. No animal studies were carried out by the authors for this article.

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Author notes

  1. Joseph J. Kim, Luqia Hou, and Guang Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Stanford Cardiovascular Institute, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5407, USA

    Joseph J. Kim, Luqia Hou, Guang Yang, Maureen Wanjare & Ngan F. Huang

  2. Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Joseph J. Kim, Luqia Hou, Guang Yang, Nicholas P. Mezak, Maureen Wanjare & Ngan F. Huang

  3. Cell Sciences Imaging Facility, Stanford University Medical School, Stanford, CA, USA

    Lydia M. Joubert

  4. Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA

    Ngan F. Huang

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Contributions

J.J.K. and N.F.H. designed the experiments. J.J.K, L.H., G.Y., N.P.M, M.W. and L.M.J. carried out the experiments. J.J.K., L.H., G.Y., and N.F.H. analyzed and interpreted the data. J.J.K., L.H., G.Y., L.M.J. and N.F.H. wrote the manuscript.

Corresponding author

Correspondence to Ngan F. Huang.

Additional information

Associate Editor Richard Waugh oversaw the review of this article.

This article is part of the 2017 CMBE Young Innovators special issue.

Ngan F. Huang is an Assistant Professor in the Department of Cardiothoracic Surgery at Stanford University and Principal Investigator at the Veterans Affairs Palo Alto Health Care System. Dr. Huang completed her BS in Chemical Engineering from the Massachusetts Institute of Technology under the research guidance of Dr. Robert Langer. She then received her MS and Ph.D. in Bioengineering from the University of California Berkeley & University of California San Francisco Joint Program in Bioengineering under the mentorship of Dr. Song Li. Prior to joining the faculty, she was a postdoctoral scholar in the Division of Cardiovascular Medicine at Stanford University under the guidance of Dr. John Cooke. Her laboratory investigates the interactions between stem cells and the extracellular matrix microenvironment for engineering cardiovascular tissues to treat cardiovascular and musculoskeletal diseases. Dr. Huang has authored over 60 publications and patents, including reports in Nat Med, PNAS, and Nano Lett. She has received numerous honors, including a NIH K99/R00 Career Development Award, Fellow of the American Heart Association, a Young Investigator award from the Society for Vascular Medicine, and a Rising Star award at the CMBE-BMES conference. Her research is funded by the NIH, Department of Defense, and Department of Veteran Affairs.

Electronic supplementary material

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12195_2017_502_MOESM1_ESM.avi

Supplementary Video 1. 3D reconstructed view of CD31 (red) and total nuclei (green) in aligned microfibrous scaffolds, based on confocal microscopy. Supplementary material 1 (AVI 244517 kb)

Supplementary material 2 (PDF 113 kb)

12195_2017_502_MOESM3_ESM.avi

Supplementary Video 2. 3D reconstructed view of CD31 (red) and total nuclei (green) in randomly oriented microfibrous scaffolds, based on confocal microscopy. Supplementary material 3 (AVI 242789 kb)

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Kim, J.J., Hou, L., Yang, G. et al. Microfibrous Scaffolds Enhance Endothelial Differentiation and Organization of Induced Pluripotent Stem Cells. Cel. Mol. Bioeng. 10, 417–432 (2017). https://doi.org/10.1007/s12195-017-0502-y

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