Cargando…

Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues

BACKGROUND: Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs...

Descripción completa

Detalles Bibliográficos
Autores principales: Murphy, Jack F., Mayourian, Joshua, Stillitano, Francesca, Munawar, Sadek, Broughton, Kathleen M., Agullo-Pascual, Esperanza, Sussman, Mark A., Hajjar, Roger J., Costa, Kevin D., Turnbull, Irene C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894319/
https://www.ncbi.nlm.nih.gov/pubmed/31801634
http://dx.doi.org/10.1186/s13287-019-1486-4
_version_ 1783476368796811264
author Murphy, Jack F.
Mayourian, Joshua
Stillitano, Francesca
Munawar, Sadek
Broughton, Kathleen M.
Agullo-Pascual, Esperanza
Sussman, Mark A.
Hajjar, Roger J.
Costa, Kevin D.
Turnbull, Irene C.
author_facet Murphy, Jack F.
Mayourian, Joshua
Stillitano, Francesca
Munawar, Sadek
Broughton, Kathleen M.
Agullo-Pascual, Esperanza
Sussman, Mark A.
Hajjar, Roger J.
Costa, Kevin D.
Turnbull, Irene C.
author_sort Murphy, Jack F.
collection PubMed
description BACKGROUND: Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs) on contractile function of human engineered cardiac tissues (hECTs) as a species-specific model of the human myocardium. METHODS: Human induced pluripotent stem cell-derived cardiomyoctes (hCMs) were mixed with Collagen/Matrigel to fabricate control hECTs, with an experimental group of hCSC-supplemented hECT fabricated using a 9:1 ratio of hCM to hCSC. Functional testing was performed starting on culture day 6, under spontaneous conditions and also during electrical pacing from 0.25 to 1.0 Hz, measurements repeated at days 8 and 10. hECTs were then frozen and processed for gene analysis using a Nanostring assay with a cardiac targeted custom panel. RESULTS: The hCSC-supplemented hECTs displayed a twofold higher developed force vs. hCM-only controls by day 6, with approximately threefold higher developed stress and maximum rates of contraction and relaxation during pacing at 0.75 Hz. The spontaneous beat rate characteristics were similar between groups, and hCSC supplementation did not adversely impact beat rate variability. The increased contractility persisted through days 8 and 10, albeit with some decrease in the magnitude of the difference of the force by day 10, but with developed stress still significantly higher in hCSC-supplemented hECT; these findings were confirmed with multiple hCSC and hCM cell lines. The force-frequency relationship, while negative for both, control (− 0.687 Hz(− 1); p = 0.013 vs. zero) and hCSC-supplemented (− 0.233 Hz(− 1);p = 0.067 vs. zero) hECTs, showed a significant rectification in the regression slope in hCSC-supplemented hECT (p = 0.011 vs. control). Targeted gene exploration (59 genes) identified a total of 14 differentially expressed genes, with increases in the ratios of MYH7/MHY6, MYL2/MYL7, and TNNI3/TNNI1 in hCSC-supplemented hECT versus controls. CONCLUSIONS: For the first time, hCSC supplementation was shown to significantly improve human cardiac tissue contractility in vitro, without evidence of proarrhythmic effects, and was associated with increased expression of markers of cardiac maturation. These findings provide new insights about adult cardiac stem cells as contributors to functional improvement of human myocardium.
format Online
Article
Text
id pubmed-6894319
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-68943192019-12-11 Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues Murphy, Jack F. Mayourian, Joshua Stillitano, Francesca Munawar, Sadek Broughton, Kathleen M. Agullo-Pascual, Esperanza Sussman, Mark A. Hajjar, Roger J. Costa, Kevin D. Turnbull, Irene C. Stem Cell Res Ther Research BACKGROUND: Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs) on contractile function of human engineered cardiac tissues (hECTs) as a species-specific model of the human myocardium. METHODS: Human induced pluripotent stem cell-derived cardiomyoctes (hCMs) were mixed with Collagen/Matrigel to fabricate control hECTs, with an experimental group of hCSC-supplemented hECT fabricated using a 9:1 ratio of hCM to hCSC. Functional testing was performed starting on culture day 6, under spontaneous conditions and also during electrical pacing from 0.25 to 1.0 Hz, measurements repeated at days 8 and 10. hECTs were then frozen and processed for gene analysis using a Nanostring assay with a cardiac targeted custom panel. RESULTS: The hCSC-supplemented hECTs displayed a twofold higher developed force vs. hCM-only controls by day 6, with approximately threefold higher developed stress and maximum rates of contraction and relaxation during pacing at 0.75 Hz. The spontaneous beat rate characteristics were similar between groups, and hCSC supplementation did not adversely impact beat rate variability. The increased contractility persisted through days 8 and 10, albeit with some decrease in the magnitude of the difference of the force by day 10, but with developed stress still significantly higher in hCSC-supplemented hECT; these findings were confirmed with multiple hCSC and hCM cell lines. The force-frequency relationship, while negative for both, control (− 0.687 Hz(− 1); p = 0.013 vs. zero) and hCSC-supplemented (− 0.233 Hz(− 1);p = 0.067 vs. zero) hECTs, showed a significant rectification in the regression slope in hCSC-supplemented hECT (p = 0.011 vs. control). Targeted gene exploration (59 genes) identified a total of 14 differentially expressed genes, with increases in the ratios of MYH7/MHY6, MYL2/MYL7, and TNNI3/TNNI1 in hCSC-supplemented hECT versus controls. CONCLUSIONS: For the first time, hCSC supplementation was shown to significantly improve human cardiac tissue contractility in vitro, without evidence of proarrhythmic effects, and was associated with increased expression of markers of cardiac maturation. These findings provide new insights about adult cardiac stem cells as contributors to functional improvement of human myocardium. BioMed Central 2019-12-04 /pmc/articles/PMC6894319/ /pubmed/31801634 http://dx.doi.org/10.1186/s13287-019-1486-4 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Murphy, Jack F.
Mayourian, Joshua
Stillitano, Francesca
Munawar, Sadek
Broughton, Kathleen M.
Agullo-Pascual, Esperanza
Sussman, Mark A.
Hajjar, Roger J.
Costa, Kevin D.
Turnbull, Irene C.
Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title_full Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title_fullStr Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title_full_unstemmed Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title_short Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
title_sort adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894319/
https://www.ncbi.nlm.nih.gov/pubmed/31801634
http://dx.doi.org/10.1186/s13287-019-1486-4
work_keys_str_mv AT murphyjackf adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT mayourianjoshua adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT stillitanofrancesca adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT munawarsadek adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT broughtonkathleenm adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT agullopascualesperanza adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT sussmanmarka adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT hajjarrogerj adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT costakevind adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues
AT turnbullirenec adulthumancardiacstemcellsupplementationeffectivelyincreasescontractilefunctionandmaturationinhumanengineeredcardiactissues