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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive May 23, 2014

 

An implanted graft of (green) cardiac cells from human stem cells merge and beat
with (red) primates' heart cells. Image Credit: Murry Lab/University of Washington

 






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Human stem cells regenerate in other primates

Heart cells created from human embryonic stem cells have successfully restored damaged heart muscles in monkeys.

The results of the experiment appear in the April 30 online edition of the journal Nature in a paper titled, "Human embryonic-stem cell derived cardiomyocytes regenerate non-human primate hearts." The findings suggest that the approach should be feasible in humans.


"Before this study, it was not known if it is possible to produce sufficient numbers of these stem cells and successfully use them to remuscularize damaged hearts in a large animal whose heart size and physiology is similar to that of the human heart."

Dr. Charles Murry, professor of pathology and bioengineering, University of Washington Center for Cardiovascular Biology, and research team leader who hopes the approach can be ready for clinical trials in humans within four years.


In the study, Dr. Murry, along with Dr. Michael Laflamme and colleagues at the UW Institute for Stem Cell & Regenerative Medicine, induced controlled myocardial infarctions, a form of heart attack, in anesthetized pigtail macaques. The infarcts were created by blocking the coronary artery of macaque for 90 minutes, an established protocol for the study of myocardial infarcts in primates.

In humans, myocardial infarctions are typically caused by coronary artery disease. This lack of adequate blood flow can damage heart muscle and other tissues by depriving them of oxygen. Because infarcted heart muscle does not grow back, myocardial infarction leaves the heart less able to pump blood and often leads to heart failure, a leading cause of death.

The goal of stem cell therapy is to replace the damaged tissue with new heart cells and restore the failing heart to normal function.

Two weeks after the experimental myocardial infarctions, the Seattle researchers injected 1 billion heart muscle cells made from human embryonic stem cells (called human embryonic stem cell-derived cardiomyocytes) into the infarcted muscle — ten times more than researchers have ever been able to generate before.

All the monkeys were on immunosuppressive therapy to prevent rejection of the transplanted human cells.

Over the following weeks, the human derived heart muscle cells infiltrated into the damaged heart tissue, matured and assembled into muscle fibers beating in synchrony with the macaque heart cells. After three months, the cells appeared to be fully integrated into the macaque hearts.

The transplanted stem cells regenerated, on average, 40 percent of the damaged heart tissue according to Dr. Michael Laflamme, assistant professor of pathology at UW whose team generated the replacement heart muscle cells.
"The results show we can produce the number of cells needed for human therapy and get formation of new heart muscle on a scale that is relevant to improving the function of the human heart."

Dr. Michael Laflamme

The most concerning complications were episodes of irregular heartbeats, or arrhythmias, occurring in the weeks following the stem cell injections. However, these symptoms disappeared after two to three weeks as stem cells matured, becomming more electrically stable.

In the future, UW researchers will work to reduce the risk of arrhythmias by using more electrically stabile stem cells. They will also work to definitively demonstrate stem cells strengthen the heart's pumping power.

"These cells have improved the mechanical function in every other species in which they have been tested, so we are optimistic they will do so in this model as well," Murry concludes.

Abstract
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 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, 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.

http://www.eurekalert.org/pub_releases/2014-04/uow-sct042814.php

James J.H. Chong was the paper's lead author. Dr. Murry was the paper's senior author. Their co-authors were Xiulan Yang, Creighton W. Don, Elina Minami, Yen-Wen Liu, Jill J Weyers,William M. Mahoney Jr., Benjamin Van Biber, Nathan J Palpant,Jay Gantz,James A. Fugate, G. Michael Gough, Keith W. Vogel, Cliff A. Astley, Charlotte E. Hotchkiss, Lil Pabon, Hans Reinecke, Edward A. Gill, Veronica Nelson, Hans-Peter Kiem, and Michael A. Laflamme.

Murry expressed gratitude to philanthropic donors who have supported UW Institute for Stem Cell & Regenerative Medicine and his work, including Jeff and Susan Brotman, Bill and Marilyn Conner, Tom and Sue Ellison, Mike and Lynn Garvey, the Oki Foundation, the Quellos Group, the Orin Smith Family Foundation and the John H. Tietze Foundation Trust.

This work was supported by NIH grants P01HL094374, R01HL084642, U01HL100405, and P01GM08619 and an Institute of Translational Health Sciences/Washington National Primate Research Center Ignition Award. J.C. was supported by National Health and Medical Research Council of Australia Overseas Training and Australian-American Fulbright Commission Fellowships. X.Y. is supported by an American Heart Association post-doctoral scholarship 12POST11940060. J.J.W is supported by an American Heart Association post-doctoral scholarship 12POST9330030. Washington National Primate Research Center is funded by the NIH, Office of Research Infrastructure Programs (ORIP P51 0D010425).


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