Pre‐treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue

Radišić, Milica; Park, Hyoungshin; Martens, Timothy P.; Salazar-Lazaro, Johanna E.; Geng, Wenliang; Wang, Yadong; Langer, Robert; Freed, Lisa E.; Vunjak-Novakovic, Gordana

doi:10.1002/jbm.a.31578

Cited by 167 publications

(167 citation statements)

References 32 publications

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“…To generate EHT, isolated rat nCMs were seeded onto collagen scaffolds, and a biphasic electrical field was applied starting at day 3 and continued throughout cultivation. As expected (14,15), cells in EHT aligned and elongated in the direction of the electrical field, and formed Cx43 junctions (Fig. 1B).…”

Section: Resultssupporting

confidence: 78%

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Song¹,

Yoon²,

Kattman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Myocardial infarction resulting in irreversible loss of cardiomyocytes (CMs) remains a leading cause of heart failure. Although cell transplantation has modestly improved cardiac function, major challenges including increasing cell survival, engraftment, and functional integration with host tissue, remain. Embryonic stem cells (ESCs), which can be differentiated into cardiac progenitors (CPs) and CMs, represent a candidate cell source for cardiac cell therapy. However, it is not known what specific cell type or condition is the most appropriate for transplantation. This problem is exasperated by the lack of efficient and predictive strategies to screen the large numbers of parameters that may impact cell transplantation. We used a cardiac tissue model, engineered heart tissue (EHT), and quantitative molecular and electrophysiological analyses, to test transplantation conditions and specific cell populations for their potential to functionally integrate with the host tissue. In this study, we validated our analytical platform using contractile mouse neonatal CMs (nCMs) and noncontractile cardiac fibroblasts (cFBs), and screened for the integration potential of ESC-derived CMs and CPs (ESC-CMs and -CPs). Consistent with previous in vivo studies, cFB injection interfered with electrical signal propagation, whereas injected nCMs improved tissue function. Purified bioreactor-generated ESC-CMs exhibited a diminished capacity for electrophysiological integration; a result correlated with lower (compared with nCMs) connexin 43 expression. ESC-CPs, however, appeared able to appropriately mature and integrate into EHT, enhancing the amplitude of tissue contraction. Our results support the use of EHT as a model system to accelerate development of cardiac cell therapy strategies.

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Section: Resultssupporting

confidence: 78%

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Song¹,

Yoon²,

Kattman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Taken together, these data support the notion that the MSCs engineered to express high levels of CXCR4 could augment therapeutic angiogenesis (34). These effects were observed using a nude rat model of MI, as in our previous studies (47) because it provides the inflammatory signals associated with the progression of MI from acute to chronic, while alleviating rejection of implanted cells.…”

Section: Effects Of Cell Delivery Platform In Rodent Models Of Acute Andsupporting

confidence: 52%

Composite scaffold provides a cell delivery platform for cardiovascular repair

Godier-Furnémont

Martens

Koeckert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Control over cell engraftment, survival, and function remains critical for heart repair. We have established a tissue engineering platform for the delivery of human mesenchymal progenitor cells (MPCs) by a fully biological composite scaffold. Specifically, we developed a method for complete decellularization of human myocardium that leaves intact most elements of the extracellular matrix, as well as the underlying mechanical properties. A cellmatrix composite was constructed by applying fibrin hydrogel with suspended cells onto decellularized sheets of human myocardium. We then implanted this composite onto the infarct bed in a nude rat model of cardiac infarction. We next characterized the myogenic and vasculogenic potential of immunoselected human MPCs and demonstrated that in vitro conditioning with a low concentration of TGF-β promoted an arteriogenic profile of gene expression. When implanted by composite scaffold, preconditioned MPCs greatly enhanced vascular network formation in the infarct bed by mechanisms involving the secretion of paracrine factors, such as SDF-1, and the migration of MPCs into ischemic myocardium, but not normal myocardium. Echocardiography demonstrated the recovery of baseline levels of left ventricular systolic dimensions and contractility when MPCs were delivered via composite scaffold. This adaptable platform could be readily extended to the delivery of other reparative cells of interest and used in quantitative studies of heart repair.biomaterial | cardiac repair | human stem cell | cardiac patch G iven the adult heart's minimal capacity for endogenous regeneration (1), cell therapy has emerged as a viable option for revascularization (2) and regeneration (3) of the infarct bed. Cell delivery methods are progressing through clinical trials, particularly in the setting of end-stage heart failure, where the lack of effective therapies leads to more than 500,000 deaths per year in the United States alone (4). Human mesenchymal stem cells (MSCs) were used with variable functional improvement and neovascularization (5-10). This outcome is thought to be largely due to the use of cell suspensions that are limited by poor cell retention (11), survival (12), engraftment (13), and differentiation (14). The underlying mechanisms (i.e., secretion of paracrine factors vs. cell incorporation) are not well defined and can be interrogated only through control over cell retention (e.g., by the use of scaffolding materials) and insight into cell phenotype (e.g., expression of functional markers). We introduce a cell delivery platform that combines a fully biological gel-matrix composite scaffold with biochemical preconditioning of human MPCs. The resulting vasculogenic and myogenic cell properties and functional benefits of the cell delivery platform were evaluated in an animal model of myocardial infarction (MI). Results and DiscussionCell Delivery Platform. Composite scaffolds for cell delivery were assembled from thin sheets of decellularized human myocardium and fibrin hydrogel. MPCs were imm...

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“…The heart consists of fibroblasts, endothelial cells, and cardiomyocytes, raising the question as to whether a certain ratio of these three cell populations supports constitution of cardiac tissues in vitro. A few reports have addressed this question systematically and most support the hypothesis that endothelial cells and fibroblasts support tissue development (12,60,71,94), but one also reported inferior outcomes in the presence of fibroblasts (50), indicating that more work is required to answer this question.…”

Section: Tissue Engineering For Cardiac Repair: Different Approachesmentioning

confidence: 99%

Physiological aspects of cardiac tissue engineering

Eschenhagen

Eder

Vollert

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac tissue engineering aims at repairing the diseased heart and developing cardiac tissues for basic research and predictive toxicology applications. Since the first description of engineered heart tissue 15 years ago, major development steps were directed toward these three goals. Technical innovations led to improved three-dimensional cardiac tissue structure and near physiological contractile force development. Automation and standardization allow medium throughput screening. Larger constructs composed of many small engineered heart tissues or stacked cell sheet tissues were tested for cardiac repair and were associated with functional improvements in rats. Whether these approaches can be simply transferred to larger animals or the human patients remains to be tested. The availability of an unrestricted human cardiac myocyte cell source from human embryonic stem cells or human-induced pluripotent stem cells is a major breakthrough. This review summarizes current tissue engineering techniques with their strengths and limitations and possible future applications.

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Pre‐treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue

Cited by 167 publications

References 32 publications

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Composite scaffold provides a cell delivery platform for cardiovascular repair

Physiological aspects of cardiac tissue engineering

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