Alignment of inducible vascular progenitor cells on a micro-bundle scaffold improves cardiac repair following myocardial infarction
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Ischemic heart disease is still the leading cause of death even with the advancement of pharmaceutical therapies and surgical procedures. Early vascularization in the ischemic heart is critical for a better outcome. Although stem cell therapy has great potential for cardiovascular regeneration, the ideal cell type and delivery method of cells have not been resolved. We tested a new approach of stem cell therapy by delivery of induced vascular progenitor cells (iVPCs) grown on polymer micro-bundle scaffolds in a rat model of myocardial infarction. iVPCs partially reprogrammed from vascular endothelial cells (ECs) had potent angiogenic potential and were able to simultaneously differentiate into vascular smooth muscle cells (SMCs) and ECs in 2D culture. Under hypoxic conditions, iVPCs also secreted angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) as measured by enzyme-linked immunosorbent assay (ELISA). A longitudinal micro-scaffold made from poly(lactic-co-glycolic acid) was sufficient for the growth and delivery of iVPCs. Co-cultured ECs and SMCs aligned well on the micro-bundle scaffold similarly as in the vessels. 3D cell/polymer micro-bundles formed by iVPCs and micro-scaffolds were transplanted into the ischemic myocardium in a rat model of myocardial infarction (MI) with ligation of the left anterior descending artery. Our in vivo data showed that iVPCs on the micro-bundle scaffold had higher survival, and better retention and engraftment in the myocardium than free iVPCs. iVPCs on the micro-bundles promoted better cardiomyocyte survival than free iVPCs. Moreover, iVPCs and iVPC/polymer micro-bundles treatment improved cardiac function (ejection fraction and fractional shortening, endocardial systolic volume) measured by echocardiography, increased vessel density, and decreased infarction size [endocardial and epicardial infarct (scar) length] better than untreated controls at 8 weeks after MI. We conclude that iVPCs grown on a polymer micro-bundle scaffold are new promising approach for cell-based therapy designed for cardiovascular regeneration in ischemic heart disease.
KeywordsVascular progenitor cells Ischemic heart diseases Stem cells Myocardial infarction Cardiovascular regeneration Micro-bundle scaffold
Our summer medical student Alisha Lall for cutting heart slides for the project. The research is funded by National Institutes of Health Grant RHL100828Z, R01 83366 (WMC), 1R01HL135110-01 (WMC,LY) and Collaborative Research and Development Projects from Austen BioInnovation Institute in Akron, OH, by Grants 14BGIA18770028 from American Heart Association and National Institutes of Health 1R15HL115540-01 (LY).
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
All animal studies were performed using protocols approved by the Northeast Ohio Medical University Institutional Animal Care and Use Committee and comply with the ethical standards laid down in the 1964 Declaration of Helsinki and all later amendments. This manuscript does not contain clinical studies or patient data.
- 2.Ban K, Park HJ, Kim S, Andukuri A, Cho KW, Hwang JW, Cha HJ, Kim SY, Kim WS, Jun HW, Yoon YS (2014) Cell therapy with embryonic stem cell-derived cardiomyocytes encapsulated in injectable nanomatrix gel enhances cell engraftment and promotes cardiac repair. ACS Nano 8:10815–10825. doi: 10.1021/nn504617g CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, El Nakadi B, Banovic M, Beleslin B, Vrolix M, Legrand V, Vrints C, Vanoverschelde JL, Crespo-Diaz R, Homsy C, Tendera M, Waldman S, Wijns W, Terzic A (2013) Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol 61:2329–2338. doi: 10.1016/j.jacc.2013.02.071 CrossRefPubMedGoogle Scholar
- 6.Cabrera-Fuentes HA, Aragones J, Bernhagen J, Boening A, Boisvert WA, Botker HE, Bulluck H, Cook S, Di Lisa F, Engel FB, Engelmann B, Ferrazzi F, Ferdinandy P, Fong A, Fleming I, Gnaiger E, Hernandez-Resendiz S, Kalkhoran SB, Kim MH, Lecour S, Liehn EA, Marber MS, Mayr M, Miura T, Ong SB, Peter K, Sedding D, Singh MK, Suleiman MS, Schnittler HJ, Schulz R, Shim W, Tello D, Vogel CW, Walker M, Li QO, Yellon DM, Hausenloy DJ, Preissner KT (2016) From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on “new frontiers in cardiovascular research”. Basic Res Cardiol 111:69. doi: 10.1007/s00395-016-0586-x CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Cheng M, Huang K, Zhou J, Yan D, Tang YL, Zhao TC, Miller RJ, Kishore R, Losordo DW, Qin G (2015) A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart. J Mol Cell Cardiol 81:49–53. doi: 10.1016/j.yjmcc.2015.01.024 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, Thistlethwaite PA (2005) Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol 46:2116–2124. doi: 10.1016/j.jacc.2005.08.045 CrossRefPubMedGoogle Scholar
- 20.Kim SW, Jin HL, Kang SM, Kim S, Yoo KJ, Jang Y, Kim HO, Yoon YS (2016) Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol 203:498–507. doi: 10.1016/j.ijcard.2015.10.110 CrossRefPubMedGoogle Scholar
- 25.Lee S, Valmikinathan CM, Byun J, Kim S, Lee G, Mokarram N, Pai SB, Um E, Bellamkonda RV, Yoon YS (2015) Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes. Biomaterials 63:158–167. doi: 10.1016/j.biomaterials.2015.06.009 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Logan SJ, Yin L, Geldenhuys WJ, Enrick MK, Stevanov KM, Carroll RT, Ohanyan VA, Kolz CL, Chilian WM (2015) Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress. Basic Res Cardiol 110:19. doi: 10.1007/s00395-015-0471-z CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Luther DJ, Thodeti CK, Shamhart PE, Adapala RK, Hodnichak C, Weihrauch D, Bonaldo P, Chilian WM, Meszaros JG (2012) Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction. Circ Res 110:851–856. doi: 10.1161/CIRCRESAHA.111.252734 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Matsuura K, Honda A, Nagai T, Fukushima N, Iwanaga K, Tokunaga M, Shimizu T, Okano T, Kasanuki H, Hagiwara N, Komuro I (2009) Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Investig 119:2204–2217. doi: 10.1172/JCI37456 PubMedPubMedCentralGoogle Scholar
- 31.Mayorga M, Kiedrowski M, Shamhart P, Forudi F, Weber K, Chilian WM, Penn MS, Dong F (2016) Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction. Am J Physiol Heart Circ Physiol 310:H20–H28. doi: 10.1152/ajpheart.00449.2015 CrossRefPubMedGoogle Scholar
- 35.Ohanyan V, Yin L, Bardakjian R, Kolz C, Enrick M, Hakobyan T, Kmetz J, Bratz I, Luli J, Nagane M, Khan N, Hou H, Kuppusamy P, Graham J, Fu FK, Janota D, Oyewumi MO, Logan S, Lindner JR, Chilian WM (2015) Requisite role of Kv1.5 channels in coronary metabolic dilation. Circ Res 117:612–621. doi: 10.1161/CIRCRESAHA.115.306642 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Suuronen EJ, Hazra S, Zhang P, Vincent R, Kumarathasan P, Zhang Y, Price J, Chan V, Sellke FW, Mesana TG, Veinot JP, Ruel M (2010) Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with l-arginine supplementation. J Thorac Cardiovasc Surg 139(209–216):e202. doi: 10.1016/j.jtcvs.2009.04.055 Google Scholar
- 46.Takagawa J, Zhang Y, Wong ML, Sievers RE, Kapasi NK, Wang Y, Yeghiazarians Y, Lee RJ, Grossman W (1985) Springer ML (2007) Myocardial infarct size measurement in the mouse chronic infarction model: comparison of area- and length-based approaches. J Appl Physiol 102:2104–2111. doi: 10.1152/japplphysiol.00033.2007 CrossRefGoogle Scholar
- 50.Woudstra L, Krijnen PA, Bogaards SJ, Meinster E, Emmens RW, Kokhuis TJ, Bollen IA, Baltzer H, Baart SM, Parbhudayal R, Helder MN, van Hinsbergh VW, Musters RJ, de Jong N, Kamp O, Niessen HW, van Dijk A, Juffermans LJ (2016) Development of a new therapeutic technique to direct stem cells to the infarcted heart using targeted microbubbles: StemBells. Stem Cell Res 17:6–15. doi: 10.1016/j.scr.2016.04.018 CrossRefPubMedGoogle Scholar
- 54.Zhang Y, Wong S, Lafleche J, Crowe S, Mesana TG, Suuronen EJ, Ruel M (2010) In vitro functional comparison of therapeutically relevant human vasculogenic progenitor cells used for cardiac cell therapy. J Thorac Cardiovasc Surg 140(216–224):e214Google Scholar