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.
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.
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.
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.
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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.
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.
Arghya Paul, PhD, is an Assistant Professor at The University of Kansas (KU) in the Department of Chemical and Petroleum Engineering, and Bioengineering Graduate Program. He is also a member of The Center for Epigenetics and Stem Cell Biology, KU Medical Center. His Biointel Research Laboratory, funded by National Institute of General Medical Sciences and State of Kansas, focuses on developing new class of nano-bioactive hydrogels, biotransporters and engineered stem cells for cardiovascular and bone research. Broadly, his work aims to (1) innovate and study transformative technologies at the biomolecular and cellular level (2) exploit the cell-matrix interactions and mechanistic pathways, and (3) discover therapeutic strategies that can be translated to point-of-care patient applications. Before joining KU, Dr. Paul completed his postdoctoral fellowship at Harvard-MIT Division of Health Sciences and Technology and Wyss Institute for Biologically Inspired Engineering, working in the areas of nanomaterials, stem cells and regeneration therapy. He received his MS and PhD degrees in Biotechnology and Biomedical Engineering from McGill University, Canada, where his research was focused on developing gene-eluting vascular stents and microengineered stem cells for cardiovascular therapy. Dr. Paul has contributed to 75 + journal articles, 15 book chapters and holds multiple invention disclosures and patents. Based on his co-patented technologies, he is currently directing MangoGen Pharma Inc., a start-up company specialized in gene delivery technologies, as Chief Scientific Officer. His academic and research achievements have been acknowledged with multiple prestigious awards, fellowships and recognitions. To name a few: Fred Kurata Memorial Professorship at KU, Raymond Oenbring Award for Excellence in Teaching Chemical Engineering, Outstanding Young Scientist (talent category) by Macromolecular Chemistry Physics journal, Banting Postdoctoral Fellowship (Canada), Postdoctoral Training Fellowship (Le Fonds de Recherche du Quebec Nature et Technologies, FRQNT), Natural Sciences and Engineering Research Council of Canada (NSERC) Alexander Graham Bell Canada Graduate Scholarship, NSERC Michael Smith Foreign Study Supplement Award, McGill Medstar Award, Leslie A. Geddes Award for Best PhD Thesis.
This article is part of the 2018 CMBE Young Innovators special issue.
Associate Editor William E. Bentley oversaw the review of this article.
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Chakravarti, A.R., Pacelli, S., Alam, P. et al. Pre-Conditioning Stem Cells in a Biomimetic Environment for Enhanced Cardiac Tissue Repair: In Vitro and In Vivo Analysis. Cel. Mol. Bioeng. 11, 321–336 (2018). https://doi.org/10.1007/s12195-018-0543-x
- Mechanical stimulation
- Myogenic differentiation
- Cardiac repair