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Cardiomyocyte transplantation after heart attack improves contractile function in monkeys. 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 transplantation of ∼750 million cryopreserved human embryonic stem cell–derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.

Regeneration of the heart muscle after myocardial infarction with cardiomyocytes derived from human embryonic stem cells is demonstrated in non-human primates, with the grafts showing evidence of electromechanical coupling, although they were also associated with non-fatal arrhythmias. Part regeneration in injured primate heart Human pluripotent stem cells have proven cardiomyocyte-generating abilities and have been extensively investigated for repair of the injured heart. There is still a long way to go before cardiac regenerative medicine can become a reality, however. In this study Charles Murry and colleagues examine the ability of exogenously delivered human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) to engraft to the host myocardium in a non-human primate model of myocardial infarction. They demonstrate large-scale heart remuscularization, electromechanical coupling of the graft to the host heart, and vascularization of the graft from host vessels. The grafts showed evidence of electromechanical coupling, but non-fatal arrhythmias were also observed in hESC-CM-engrafted primates. Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure 1 by providing human cardiomyocytes to support heart regeneration 2 . Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment 3 , 4 , 5 , 6 , 7 . However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models 7 , non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD. Allogeneic hematopoietic cell transplantation (allo-HCT) has led to the cure of HIV in one individual, but the underlying mechanisms are unclear. Here, the authors present a model of allo-HCT in SHIV-infected nonhuman primates and show that the SHIV reservoir persists in multiple tissues early after transplantation.

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 transplantation of 750 million cryopreserved human embryonic stem cell–derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6±0.9% vs. 2.5±0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart and by 3 months contained 99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.

Nat. Biotechnol. 36, 597–605 (2018); published online 2 July 2018; corrected after print 18 July 2018 In the version of this article initially published, NIH grant P51 OD010425 was omitted. The error has been corrected in the HTML and PDF versions of the article.

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-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intramyocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

September 2001 marked the fiftieth anniversary of the signing of the San Francisco Treaty, formally ending the Second World War. In signing this treaty, Japan fundamentally transformed its position on the world stage. It established itself in the vanguard of the burgeoning cold war bulwark against the Soviet Union and its communist satellites, and wed itself to the United States through economic, political, and security ties that persist today. The half century since the establishment of the San Francisco system has seen highs and lows in the relations between the two countries, continuing even into the current war on terrorism. This new book evaluates the changing relationship between the two great powers, providing in-depth analysis on a variety of topics. It scrutinizes the historical context, providing the reader with predictive tools for understanding events as they unfold. Instead of looking at the U.S.-Japan relationship one issue at a time, this book examines specific trends and then analyzes how these trends affect the relationship as a whole. This innovative approach allows the reader to view several perspectives simultaneously, and it compels the contributors to assemble clear causal arguments that detail what each factor can and cannot explain. The result is a cogent and convincing appraisal of the status and future of U.S.-Japan relations after fifty years of peaceful coexistence.

The announced shipping campaign from Fernald will greatly increase the rate of waste-bearing trucks rolling across highways. In addition, the more potent levels of uranium-tainted waste containing a radioactive derivative, radium-226, will require thicker shielding than containers holding previous waste loads from Fernald. He noted the Utah Legislature last year \"classified this as hotter than the normal waste\" disposed of in a privately run waste facility there. Lawmakers refused to give the facility the necessary authorization to take the Fernald waste, [Bob Loux] said. From October this year through November 2005, the Department of Energy plans to ship 15 truckloads per day of potent, low-level radio-active waste from the defunct Ferald, Ohio nuclear weapons facility to the Nevada Test Site. The waste, a by-product from processing high-grade, African Congo uranium ore, has been stored in two silos at the Fernald site since the 1950s.

Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. Here, we show a major genetic effect on rhythmic methylation in a mouse Snord116 deletion model of the imprinted disorder Prader–Willi syndrome (PWS). More than 23,000 diurnally rhythmic CpGs are identified in wild-type cortex, with nearly all lost or phase-shifted in PWS. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus is observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of cross-talk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and are enriched for PWS-relevant phenotypes and pathways. These results support the proposed evolutionary relationship between imprinting and sleep, and suggest possible chronotherapy in the treatment of PWS and related disorders. Many genes have oscillating gene expression pattern in circadian centers of the brain. This study shows cortical diurnal DNA methylation oscillation in a mouse model of Prader-Willi syndrome, and describes corresponding changes in gene expression and chromatin compaction.

Background Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with a shift towards a more adaptive or proreparative state induced by the SCI. A potential link is SCI-induced inflammation, which is elevated in the subacute period, and, as injection of lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia may play a role in LPS-mediated plasticity as they react to LPS and are implicated in facilitating recovery following SCI. However, it is unknown how microglia change in response to LPS following SCI to promote neuroplasticity. Main body Here we used single-cell RNA sequencing to examine microglial responses in subacute and chronic SCI with and without an LPS injection. We show that subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states. DAM states exhibit predicted metabolic pathway activity and neuronal interactions that are associated with potential mediators of plasticity. With LPS injection, microglia shifted away from the homeostatic signature to a primed, translation-associated state and increased DAM in degenerated tracts caudal to the injury. Conclusion Microglial states following an inflammatory stimulus in chronic injury incompletely recapitulate the subacute injury environment, showing both overlapping and distinct microglial signatures across time and with LPS injection. Our results contribute to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI.