Dataset Information

Emergent Global Contractile Force in Cardiac Tissues.

ABSTRACT: The heart is a complex organ whose structure and function are intricately linked at multiple length scales. Although several advancements have been achieved in the field of cardiac tissue engineering, current in vitro cardiac tissues do not fully replicate the structure or function necessary for effective cardiac therapy and cardiotoxicity studies. This is partially due to a deficiency in current understandings of cardiac tissue organization's potential downstream effects, such as changes in gene expression levels. We developed a novel (to our knowledge) in vitro tool that can be used to decouple and quantify the contribution of organization and associated downstream effects to tissue function. To do so, cardiac tissue monolayers were designed into a parquet pattern to be organized anisotropically on a local scale, within a parquet tile, and with any desired organization on a global scale. We hypothesized that if the downstream effects were muted, the relationship between developed force and tissue organization could be modeled as a sum of force vectors. With the in vitro experimental platforms of parquet tissues and heart-on-a-chip devices, we were able to prove this hypothesis for both systolic and diastolic stresses. Thus, insight was gained into the relationship between the generated stress and global myofibril organization. Furthermore, it was demonstrated that the developed quantitative tool could be used to estimate the changes in stress production due to downstream effects decoupled from tissue architecture. This has the potential to elucidate properties coupled to tissue architecture, which change force production and pumping function in the diseased heart or stem cell-derived tissues.

SUBMITTER: Knight MB

PROVIDER: S-EPMC4833833 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Emergent Global Contractile Force in Cardiac Tissues.

Knight Meghan B MB Drew Nancy K NK McCarthy Linda A LA Grosberg Anna A

Biophysical journal 20160401 7

The heart is a complex organ whose structure and function are intricately linked at multiple length scales. Although several advancements have been achieved in the field of cardiac tissue engineering, current in vitro cardiac tissues do not fully replicate the structure or function necessary for effective cardiac therapy and cardiotoxicity studies. This is partially due to a deficiency in current understandings of cardiac tissue organization's potential downstream effects, such as changes in gen ...[more]

PMID: 27074686

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Project 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.

Dataset Information

Emergent Global Contractile Force in Cardiac Tissues.

Publications

Emergent Global Contractile Force in Cardiac Tissues.

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