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Cellular and Molecular Bioengineering

, Volume 11, Issue 5, pp 321–336 | Cite as

Pre-Conditioning Stem Cells in a Biomimetic Environment for Enhanced Cardiac Tissue Repair: In Vitro and In Vivo Analysis

  • Aparna R. Chakravarti
  • Settimio Pacelli
  • Perwez Alam
  • Samik Bagchi
  • Saman Modaresi
  • Andras Czirok
  • Rafeeq P. H. Ahmed
  • Arghya PaulEmail author
Article

Abstract

Introduction

Stem cell-based therapies represent a valid approach to restore cardiac function due to their beneficial effect in reducing scar area formation and promoting angiogenesis. However, their translation into the clinic is limited by the poor differentiation and inability to secrete sufficient therapeutic factors. To address this issue, several strategies such as genetic modification and biophysical pre-conditioning have been used to enhance the efficacy of stem cells for cardiac tissue repair.

Methods

In this study, a biomimetic approach was used to mimic the natural mechanical stimulation of the myocardium tissue. Specifically, human adipose-derived stem cells (hASCs) were cultured on a thin gelatin methacrylamide (GelMA) hydrogel disc and placed on top of a beating cardiomyocyte layer. qPCR studies and metatranscriptomic analysis of hASCs gene expression were investigated to confirm the correlation between mechanical stimuli and cardiomyogenic differentiation. In vivo intramyocardial delivery of pre-conditioned hASCs was carried out to evaluate their efficacy to restore cardiac function in mice hearts post-myocardial infarction.

Results

The cyclic strain generated by cardiomyocytes significantly upregulated the expression of both mechanotransduction and cardiomyogenic genes in hASCs as compared to the static control group. The inherent angiogenic secretion profile of hASCs was not hindered by the mechanical stimulation provided by the designed biomimetic system. Finally, in vivo analysis confirmed the regenerative potential of the pre-conditioned hASCs by displaying a significant improvement in cardiac function and enhanced angiogenesis in the peri-infarct region.

Conclusion

Overall, these findings indicate that cyclic strain provided by the designed biomimetic system is an essential stimulant for hASCs cardiomyogenic differentiation, and therefore can be a potential solution to improve stem-cell based efficacy for cardiovascular repair.

Keywords

Mechanical stimulation Myogenic differentiation Angiogenesis Cardiac repair 

Notes

Acknowledgments

AP acknowledges an investigator grant provided by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the NIH Award Number P20GM103638 and Umbilical Cord Matrix Project fund from State of Kansas. RPHA acknowledges the support from National Institute of Health (NIH) Grant 1R01HL-10690. AC acknowledges support from AHA 16GRNT31030030 and NIH GM102801. Research reported in this publication was made possible by the services of Dr. Erik Lundquist and Ms. Jennifer Hackett at the KU Genome Sequencing Core. The authors also acknowledge the services provided by Dr. Stuart Macdonald and Ms. Boryana S Koseva at the KU-INBRE Bioinformatics Core. This core lab is supported by an Institutional Development Award (IDeA) from the NIGMS (P20GM103418) from the NIH. We also gratefully thank Ms. Heather Shinogle of the University of Kansas Microscopy and Analytical Imaging Laboratory for her assistance with confocal fluorescence microscopy. We further acknowledge Ms. Dona Gréta Isai from the University of Kansas Medical Center for her help in the non-invasive image analysis of cardiomyocytes contractility.

Conflict of interest

Aparna R. Chakravarti, Settimio Pacelli, Perwez Alam, Samik Bagchi, Saman Modaresi, Andras Czirok, Rafeeq P.H. Ahmed, and Arghya Paul declare no conflict of interests.

Ethical Standards

All animal studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23 revised 1985) and approved by IACUC. No human studies were carried out by the authors for this article. Only commercially obtained cells were used.

Supplementary material

12195_2018_543_MOESM1_ESM.docx (206 kb)
Supplementary material 1 (DOCX 206 kb)

Supplementary material 2 (WMV 12,122 kb)

Supplementary material 3 (WMV 60,309 kb)

Supplementary material 4 (WMV 41,200 kb)

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Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  1. 1.Biointel Research Laboratory, Department of Chemical and Petroleum Engineering, School of EngineeringUniversity of KansasLawrenceUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of CincinnatiCincinnatiUSA
  3. 3.Department of Civil, Environmental, and Architectural EngineeringUniversity of KansasLawrenceUSA
  4. 4.Department of Anatomy and Cell BiologyUniversity of Kansas, Medical CenterKansas CityUSA
  5. 5.Water Technology GroupBlack and Veatch CorporationWalnut CreekUSA

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