Abstract:
RATIONALE:One goal of cardiac tissue engineering is the generation of a living, human pump in vitro that could replace animal models and eventually serve as an in vivo therapeutic. Models that replicate the geometrically complex structure of the heart, harboring chambers and large vessels with soft biomaterials, can be achieved using 3-dimensional bioprinting. Yet, inclusion of contiguous, living muscle to support pump function has not been achieved. This is largely due to the challenge of attaining high densities of cardiomyocytes-a notoriously nonproliferative cell type. An alternative strategy is to print with human induced pluripotent stem cells, which can proliferate to high densities and fill tissue spaces, and subsequently differentiate them into cardiomyocytes in situ. OBJECTIVE:To develop a bioink capable of promoting human induced pluripotent stem cell proliferation and cardiomyocyte differentiation to 3-dimensionally print electromechanically functional, chambered organoids composed of contiguous cardiac muscle. METHODS AND RESULTS:We optimized a photo-crosslinkable formulation of native ECM (extracellular matrix) proteins and used this bioink to 3-dimensionally print human induced pluripotent stem cell-laden structures with 2 chambers and a vessel inlet and outlet. After human induced pluripotent stem cells proliferated to a sufficient density, we differentiated the cells within the structure and demonstrated function of the resultant human chambered muscle pump. Human chambered muscle pumps demonstrated macroscale beating and continuous action potential propagation with responsiveness to drugs and pacing. The connected chambers allowed for perfusion and enabled replication of pressure/volume relationships fundamental to the study of heart function and remodeling with health and disease. CONCLUSIONS:This advance represents a critical step toward generating macroscale tissues, akin to aggregate-based organoids, but with the critical advantage of harboring geometric structures essential to the pump function of cardiac muscle. Looking forward, human chambered organoids of this type might also serve as a test bed for cardiac medical devices and eventually lead to therapeutic tissue grafting.
journal_name
Circ Resjournal_title
Circulation researchauthors
Kupfer ME,Lin WH,Ravikumar V,Qiu K,Wang L,Gao L,Bhuiyan DB,Lenz M,Ai J,Mahutga RR,Townsend D,Zhang J,McAlpine MC,Tolkacheva EG,Ogle BMdoi
10.1161/CIRCRESAHA.119.316155subject
Has Abstractpub_date
2020-07-03 00:00:00pages
207-224issue
2eissn
0009-7330issn
1524-4571journal_volume
127pub_type
杂志文章abstract::Radiolabeled triiodothyronine (T3) binding to isolated nuclei was measured to compare the binding characteristics of the nuclear receptors in rabbit ventricular and atrial muscle cells. Scatchard analysis of the binding data yielded a maximum binding capacity of 170 +/- 20 fmol per mg DNA and apparent dissociation con...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.1.267
更新日期:1988-07-01 00:00:00
abstract::Previous studies have demonstrated that low shear rates promote leukocyte adherence to microvascular endothelium in postcapillary venules. The objective of this study was to determine whether an accumulation of inflammatory mediators such as platelet activating factor and leukotriene B4 is responsible for shear rate-d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.4.906
更新日期:1992-10-01 00:00:00
abstract::In the mammalian myocardium, potassium (K(+)) channels control resting potentials, action potential waveforms, automaticity, and refractory periods and, in most cardiac cells, multiple types of K(+) channels that subserve these functions are expressed. Molecular cloning has revealed the presence of a large number of K...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/hh2301.100349
更新日期:2001-11-23 00:00:00
abstract:RATIONALE:Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung e...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.195883
更新日期:2009-09-11 00:00:00
abstract:RATIONALE:Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs). OBJECTIVE:To determine whether hyperglycemia in vitro and diabetes in vivo promote vascular BMP activity and c...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.236596
更新日期:2011-02-18 00:00:00
abstract::The adenosine analogue phenylisopropyladenosine decreased the basal and isoproterenol-stimulated contractile state of isolated rat left atria. The ED50 levels for both responses were similar, suggesting that direct and antiadrenergic effects may be mediated by the same receptor. Phenylisopropyladenosine decreased the ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.56.5.728
更新日期:1985-05-01 00:00:00
abstract::We examined the late coronary vascular response to carotid chemoreceptor reflex activation in normal, conscious dogs instrumented for the measurement of right main and left circumflex coronary artery blood flows, arterial and right ventricular pressures, and arterial and coronary sinus blood gases and O2 contents. Wit...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.54.1.96
更新日期:1984-01-01 00:00:00
abstract::Adenosine, a vasodilator metabolite, is often produced in tissues where the demand for oxygen exceeds the supply. We have recently demonstrated in isolated cannulated arterioles that adenosine and its metabolite, inosine, can also cause vasoconstriction by stimulation of mast cells. Secondary release of histamine and ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.78.4.627
更新日期:1996-04-01 00:00:00
abstract::Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual's body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000014226.74709.90
更新日期:2002-04-05 00:00:00
abstract::Recent studies have shown that the primary heart tube continues to grow by addition of cells from the coelomic wall. This growth occurs concomitantly with embryonic folding and formation of the coelomic cavity, making early heart formation morphologically complex. A scarcity of data on localized growth parameters furt...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.185843
更新日期:2009-01-30 00:00:00
abstract::High affinity binding sites of angiotensin II (A II) have been characterized in rabbit renomedullary interstitial cells in tissue culture. Binding was rapid, specific, and saturable. Scatchard analysis of steady state saturation binding data at 22 degrees C indicated a single binding site with an equilibrium dissociat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.46.6.802
更新日期:1980-06-01 00:00:00
abstract::To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.2.256
更新日期:1987-08-01 00:00:00
abstract::Two gap junction proteins, connexin43 (Cx43) and connexin45 (Cx45), are coexpressed in many cardiac and other cells. Homomeric channels formed by these proteins differ in unitary conductance, permeability, and regulation. We sought to determine the ability of Cx43 and Cx45 to oligomerize with each other to form hetero...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000019580.64013.31
更新日期:2002-05-31 00:00:00
abstract::Over the last 4 decades, heart transplantation (HTx) has evolved as a mainstream therapy for heart failure. Approximately half of patients needing HTx have organ failure consequent to atherosclerosis. Despite advances in immunosuppressive drugs, long-term success of HTx is limited by the development of a particular ty...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.RES.0000246086.93555.f3
更新日期:2006-10-13 00:00:00
abstract::We have investigated the requirement for c-myc downregulation in the growth arrest of vascular smooth muscle cells (VSMCs). Rat VSMCs were infected with a retrovirus vector directing constitutive expression of either the complete human c-Myc protein (VSM-myc cells) or the c-Myc deletion mutant D106-143, which is inact...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.3.525
更新日期:1994-03-01 00:00:00
abstract::We tested a number of hypotheses concerning the mechanism of K+-induced vasodilation of the coronary vascular bed. Blood flow in the circumflex artery was measured in pentobarbital-anesthetized, open-chest dogs. Intracircumflex artery bolus injections of 40 mumol of isomotic KCl produced decreases in coronary vascular...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.42.1.35
更新日期:1978-01-01 00:00:00
abstract:RATIONALE:Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.300285
更新日期:2013-03-01 00:00:00
abstract::Transient coronary occlusion (15 minutes) does not result in irreversible myocardial injury but is associated with a depression of contractile function sustained for several hours to days ("stunned myocardium"). The defect in the contractile process responsible for this phenomenon has been suggested to be causally rel...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.6.834
更新日期:1987-12-01 00:00:00
abstract::Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by wh...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.4.493
更新日期:1997-10-01 00:00:00
abstract::Mitochondria are an important source of reactive oxygen species (ROS), implicated in ischemia/reperfusion injury. When isolated from ischemic myocardium, mitochondria demonstrate increased ROS production as a result of damage to electron transport complexes. To investigate the mechanisms, we studied effects of hypoxia...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.180869
更新日期:2008-10-10 00:00:00
abstract::A period of prolonged vasodilation follows flow-restricted exercise of skeletal muscle. We tested the hypothesis that adenosine participates in mediating this vascular response. Vascularly isolated, anterior calf muscles of anesthetized dogs were stimulated to contract at a rate of 4 twitches/sec. Blood flow was held ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.44.6.759
更新日期:1979-06-01 00:00:00
abstract::We tested the hypothesis that impairment of flow-dependent dilator mechanisms of skeletal muscle arterioles is one of the underlying reasons for the increased peripheral resistance in hypertension. Isolated, cannulated arterioles (approximately 55 microns) of gracilis muscle of 12-week-old spontaneously hypertensive (...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.3.416
更新日期:1994-03-01 00:00:00
abstract::Many members of the two-pore-domain potassium (K(+)) channel family have been detected in the mammalian heart but the endogenous correlates of these channels still have to be identified. We investigated whether I(KAA), a background K(+) current activated by negative pressure (stretch) and by arachidonic acid (AA) and ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh1601.094979
更新日期:2001-08-17 00:00:00
abstract::The mechanism of adenosine-induced inhibition of Ca2+ currents was studied by recording single-channel Ca2+ currents from cell-attached patches on isolated guinea pig ventricular cells with pipettes containing 50 or 100 mM Ba2+. Numerous 100-msec depolarization steps were applied repetitively at 2 Hz from the resting ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.67.5.1134
更新日期:1990-11-01 00:00:00
abstract:RATIONALE:Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation. OBJECTIVE:To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.302089
更新日期:2014-01-03 00:00:00
abstract:RATIONALE:The recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.120.317372
更新日期:2021-01-08 00:00:00
abstract::Peripheral blood (PB)-derived CD14+ monocytes were shown to transdifferentiate into endothelial cell (EC) lineage cells and contribute to neovascularization. We investigated whether bone marrow (BM)- or PB-derived CD34-/CD14+ cells are involved in reendothelialization after carotid balloon injury. Although neither hem...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000099245.08637.CE
更新日期:2003-11-14 00:00:00
abstract::-The vascular endothelial growth factor receptor Flk-1/KDR is highly expressed during development and almost disappears in adult tissues. Despite its biological relevance, little is known about the molecular mechanisms controlling its expression. In the present work, it is shown that cAMP response element binding prot...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:2000-06-23 00:00:00
abstract::The aging population is increasing in developed countries. Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypert...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.116.307474
更新日期:2016-05-13 00:00:00
abstract::Five fetal sheep (gestational age, 118 to 125 days) were instrumented to measure impedances of the lower abdominal aorta. Four days after surgery, flow and pressure pulses were recorded during control conditions and during infusion of norepinephrine (0.3 to 3 micrograms.min-1.kg-1 body weight) or angiotensin II (0.2 t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.4.641
更新日期:1994-04-01 00:00:00