Hans Reinecke

Hans Reinecke
University of Washington Seattle | UW · Center for Cardiovascular Biology

Ph.D.

About

109
Publications
12,260
Reads
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15,327
Citations
Additional affiliations
January 2010 - present
University of Washington Seattle
Position
  • Senior Researcher
September 1996 - present
University of Washington Seattle
Position
  • Senior Researcher
February 1991 - August 1995
University of Freiburg
Position
  • PhD Student

Publications

Publications (109)
Article
Full-text available
Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythm...
Preprint
Full-text available
Background: Engraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation. Objectives We hypothesized that clinically approved antiarr...
Article
Full-text available
COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that...
Preprint
Full-text available
Global health has been threatened by the COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Although considered primarily a respiratory infection, many COVID-19 patients also suffer severe cardiovascular disease. Improving patient care critically relies on understanding if cardiovascular pathology is...
Article
Human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) applications for cell therapy and disease modeling are limited due to the cells’ lack of resemblance structurally and functionally to adult cardiomyocytes. To understand hPSC-CM maturation, we characterized two established approaches to mature cardiomyocytes—long term culture (aging of cel...
Article
Full-text available
The engraftment of human stem cell-derived cardiomyocytes (hSC-CMs) is a promising treatment for remuscularizing the heart wall post-infarction, but it is plagued by low survival of transplanted cells. We hypothesize that this low survival rate is due to continued ischemia within the infarct, and that increasing the vascularization of the scar will...
Article
Background: The giant sarcomere protein titin is important in both heart health and disease. Mutations in the gene encoding for titin (TTN) are the leading known cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within TTN motivated us to seek a more complete understanding of this gene and the isoforms it encodes...
Article
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Although human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a novel platform for heart regeneration, disease modeling, and drug screening, their immaturity significantly hinders their application. A hallmark of postnatal cardiomyocyte maturation is the metabolic substrate switch from glucose to fatty acids. We hypothesize...
Article
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Functional changes in spatial genome organization during human development are poorly understood. Here we report a comprehensive profile of nuclear dynamics during human cardiogenesis from pluripotent stem cells by integrating Hi-C, RNA-seq and ATAC-seq. While chromatin accessibility and gene expression show complex on/off dynamics, large-scale gen...
Article
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Highlights • Many cardiomyopathy families have genetic variants whose significance is unknown. We studied a novel (E848G) mutation in MYH7, a sarcomeric protein. • Patient-specific induced pluripotent stem cell–derived cardiomyocytes and engineered heart tissues recapitulated the contractile dysfunction. • Overexpression of the E848G allele in MYH7...
Preprint
Full-text available
Background: Despite modern pharmacotherapy, heart failure remains a major medical burden. The heart has a limited regenerative capacity, and bolstering regeneration might represent new therapeutic approaches for heart failure patients. Various progenitor cells in the heart have been proposed to have cardiomyogenic properties, but this evidence is b...
Article
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Pluripotent stem cell–derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transpl...
Article
To easily edit the genome of naïve human embryonic stem cells (hESC), we introduced a dual cassette encoding an inducible Cas9 into the AAVS1 site of naïve hESC (iCas9). The iCas9 line retained karyotypic stability, expression of pluripotency markers, differentiation potential, and stability in 5iLA and EPS pluripotency conditions. The iCas9 line i...
Preprint
Full-text available
While chromosomal architecture varies among cell types, little is known about how this organization is established or its role in development. We integrated Hi-C, RNA-seq and ATAC-seq during cardiac differentiation from human pluripotent stem cells to generate a comprehensive profile of chromosomal architecture. We identified active and repressive...
Article
The giant sarcomeric protein titin has numerous important roles in cardiomyocytes, including providing passive tension and facilitating myofibril formation. An internal promoter has recently been identified in the titin gene (TTN) that is predicted to regulate expression of a previously unstudied isoform, Cronos. To study the role of Cronos titin i...
Article
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We hypothesized that the neonatal rat heart would bring transplanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to maturity as it grows to adult size. In neonatal rat heart, engrafted hiPSC derivatives developed partially matured myofibrils after 3 months, with increasing cell size and sarcomere length. There was no diff...
Article
Full-text available
Backgrounds: -Tissue engineering enables the generation of functional human cardiac tissue using cells derived in vitro in combination with biocompatible materials. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications....
Article
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Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts. We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performe...
Article
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Impaired systolic function, resulting from acute injury or congenital defects, leads to cardiac complications and heart failure. Current therapies slow disease progression but do not rescue cardiac function. We previously reported that elevating the cellular 2 deoxy-ATP (dATP) pool in transgenic mice via increased expression of ribonucleotide reduc...
Article
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Background: Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. Objective: We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Methods: Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac diffe...
Article
Heart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model...
Article
Recent advances in pluripotent stem cell biology and directed differentiation have identified a population of human cardiovascular progenitors that give rise to cardiomyocytes, smooth muscle and endothelial cells. Because the heart develops from progenitors in 3-D under constant mechanical load, we sought to test the effects of a 3-D microenvironme...
Article
Full-text available
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-sc...
Article
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have great potential as a cell source for therapeutic applications such as regenerative medicine, disease modeling, drug screening, and toxicity testing. This potential is limited, however, by the immature state of the cardiomyocytes acquired using current protocols. Tri-i...
Article
Full-text available
The main objective of cell therapy is regeneration of damaged tissues. To distinguish graft from host tissue by magnetic resonance imaging (MRI), a paramagnetic label must be introduced to cells prior to transplantation. The paramagnetic label can be either exogenous iron oxide nanoparticles or a genetic overexpression of ferritin, an endogenous ir...
Article
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of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indiana, USA, August 4 – August 8, 2013.
Article
Objective: Intimal hyperplasia is considered to be a healing response and is a major cause of vessel narrowing after injury, where migration of vascular progenitor cells contributes to pathological events, including transplant arteriosclerosis. Approach and results: In this study, we used a rat aortic-allograft model to identify the predominant...
Article
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Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors play instrumental roles in embryonic organogenesis and diseases of adult organs. In particular, PDGFRα is expressed by multi-potent cardiovascular progenitors in mouse and human embryonic stem cell systems. Although cardiac PDGFRα expression has been studied in multiple spe...
Article
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The noninvasive detection of transplanted cells in damaged organs and the longitudinal follow-up of cell fate and graft size are important for the evaluation of cell therapy. We have shown previously that the overexpression of the natural iron storage protein, ferritin, permits the detection of engrafted cells in mouse heart by MRI, but further ima...
Article
Directed differentiation of human embryonic stem cells (ESCs) into cardiovascular cells provides a model for studying molecular mechanisms of human cardiovascular development. Although it is known that chromatin modification patterns in ESCs differ markedly from those in lineage-committed progenitors and differentiated cells, the temporal dynamics...
Article
Full-text available
Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has n...
Article
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Background: Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro-fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. Methods: We used a TSP-2 knockout (KO...
Article
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Poor cell retention and limited cell survival after grafting are major limitations of cell therapy. Recent studies showed that the use of matrices as vehicles at the time of cell injection can significantly improve cell engraftment by providing an appropriate structure and physical support for the injected cells. Properly designed matrices can also...
Article
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A peroxisome proliferator-actived receptor (PPAR) response element (RE) in the promoter region of the adaptor-related protein complex 2, alpha 2 subunit (AP2α2) of mouse heart has been identified. The steroid hormone nuclear PPARs and the retinoid X receptors (RXRs) are important transcriptional factors that regulate gene expression, cell different...
Article
The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human heart growth by these processes is poorly understood. We seek to elucidate the responses of immature human myocardium to mechanical load and vascularization using tissue engineering approaches. Using human embryonic stem cell...
Chapter
Cellular cardiomyoplasty describes the procedure of cell delivery to the injured heart with the goal to either reverse or at least halt the detrimental effects of myocardial injury. Several strategies for cell delivery to the injured myocardium are available. Direct intramyocardial injection may be performed using a transepicardial, surgical, trans...
Article
Full-text available
An unmet need in cardiac cell therapy is a noninvasive imaging technique capable of tracking changes in graft size over time and monitoring cell dynamics such as replication and death, factors to which commonly used superparamagnetic nanoparticles are insensitive. Our goal was to explore if overexpression of ferritin, a nontoxic iron-binding protei...
Data
β-catenin is present in the nuclei of undifferentiated ES cells and early differentiated cells. Shown are Western blots of cytoplasmic and nuclear fractions from day 0 (undifferentiated) and day 2 (mesoderm) cells. Probing for β-catenin shows robust expression in both the cytoplasmic and nuclear fractions at both timepoints. Also shown is β-actin a...
Data
Early Wnt/β-catenin signaling does not affect other cardiovascular lineages during cardiac directed differentiation. Quantitative RT-PCR on day 14 of differentiation shows a small induction of SM22α and VE-cadherin by activin A/BMP4 treatment. These effects are not significantly altered by treatment with either Wnt3a or Dkk1. (0.67 MB TIF)
Data
Early Wnt/β-catenin signaling has a modest effect on apoptosis and proliferation. (A) Shown are both adherent and non-adherent cell counts from 3 wells of a 24-well plate for each treatment group. (B) Samples were analyzed by flow cytometry for annexin V to identify apoptotic cells. (C) Samples were incubated with propidium iodide and analyzed by f...
Article
Full-text available
Wnt/beta-catenin signaling is an important regulator of differentiation and morphogenesis that can also control stem cell fates. Our group has developed an efficient protocol to generate cardiomyocytes from human embryonic stem (ES) cells via induction with activin A and BMP4. We tested the hypothesis that Wnt/beta-catenin signals control both earl...
Article
Cell transplantation improves cardiac function after myocardial infarction; however, the underlying mechanisms are not well-understood. Therefore, the goals of this study were to determine if neonatal rat cardiomyocytes transplanted into adult rat hearts 1 week after infarction would, after 8-10 weeks: 1) improve global myocardial function, 2) cont...
Article
Full-text available
Success of human myocardial tissue engineering for cardiac repair has been limited by adverse effects of scaffold materials, necrosis at the tissue core, and poor survival after transplantation due to ischemic injury. Here, we report the development of scaffold-free prevascularized human heart tissue that survives in vivo transplantation and integr...
Article
In recent years, cell transplantation has drawn tremendous interest as a novel approach to preserving or even restoring contractile function to infarcted hearts. A typical human infarct involves the loss of approximately 1 billion cardiomyocytes, and, therefore, many investigators have sought to identify endogenous or exogenous stem cells with the...
Article
Stem cell differentiation involves changes in transcription, but little is known about translational control during differentiation. We comprehensively profiled gene expression during differentiation of murine embryonic stem cells (ESCs) into embryoid bodies by integrating transcriptome analysis with global assessment of ribosome loading. While pro...
Article
Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing a...