29 May 2012

Transforming Human Stem Cells to Cardiomyocytes Promises Efficient and Inexpensive Heart Treatments

A single human cardiomyocyte grown using a method devised by UW-Madison chemical and biological engineering graduate student Xiaojun Lian. Cardiomyocytes, the workhorse muscle cells of the heart, can now be grown cheaply and abundantly in the lab, thanks to the new method devised by Lian and his colleagues.
Image credit: Xiaojun Lian
Stem cells are cells found in the body that have the capability to transform itself into any type of biological cell in the body.

In terms of human stem cells, these cells can be made into various human cells and tissues. This technology has great potential to treat otherwise untreatable diseases and conditions. Stem cells can repair and even replace diseased cells in organs and tissues. It can even assist in organ regeneration.

Stem cells are taken from human embryos about four or five days after fertilization. That stage of the embryo is called the late blastocyst stage.

The blastocyst contains three distinct areas:
  • Trophoblast - surrounding outer layer that later becomes the placenta
  • Blastocoel - fluid-filled cavity within the blastocyst
  • Embryoblast - the inner cell mass which can become the embryo or fetus.

Embryonic stem cells can be created from cells taken from the inner cell mass Because these cells are taken from such an early stage in development, they have the ability to become cells of any tissue type (except for the whole embryo itself), making them pluripotent.

Pluripotent cells are cells that has the potential to differentiate into any of the three cell groupings or germ layers:
  • Endoderm (interior stomach lining, gastrointestinal tract, the lungs)
  • Mesoderm (muscle, bone, blood, urogenital)
  • Ectoderm (epidermal tissues and nervous system).

Because of the manner that stem cells are procured, arguments have been raised on the morality of sacrificing an embryo for disease research and treatment.

New stem cell technique promises abundance of key heart cells

Cardiomyocytes, the workhorse cells that make up the beating heart, can now be made cheaply and abundantly in the laboratory.

Writing in the Proceedings of the National Academy of Sciences, a team of Wisconsin scientists describes a way to transform human stem cells -- both embryonic and induced pluripotent stem cells -- into the critical heart muscle cells by simple manipulation of one key developmental pathway. The technique promises a uniform, inexpensive and far more efficient alternative to the complex bath of serum or growth factors now used to nudge blank slate stem cells to become specialized heart cells.

"Our protocol is more efficient and robust," explains Sean Palecek, the senior author of the new report and a University of Wisconsin-Madison professor of chemical and biological engineering. "We have been able to reliably generate greater than 80 percent cardiomyocytes in the final population while other methods produce about 30 percent cardiomyocytes with high batch-to-batch variability."

Video: Stem Cells and the Heart

The ability to make the key heart cells in abundance and in a precisely defined way is important because it shows the potential to make the production of large, uniform batches of cardiomyocytes routine, according to Palecek. The cells are in great demand for research, and increasingly for the high throughput screens used by the pharmaceutical industry to test drugs and potential drugs for toxic effects.

The capacity to make the heart cells using induced pluripotent stem cells, which can come from adult patients with diseased hearts, means scientists will be able to more readily model those diseases in the laboratory. Such cells contain the genetic profile of the patient, and so can be used to recreate the disease in the lab dish for study. Cardiomyocytes are difficult or impossible to obtain directly from the hearts of patients and, when obtained, survive only briefly in the lab.

Scientists also have high hopes that one day healthy lab-grown heart cells can be used to replace the cardiomyocytes that die as a result of heart disease, the leading cause of death in the United States.

"Many forms of heart disease are due to the loss or death of functioning cardiomyocytes, so strategies to replace heart cells in the diseased heart continue to be of interest," notes Timothy Kamp, another senior author of the new PNAS report and a professor of cardiology in the UW School of Medicine and Public Health. "For example, in a large heart attack up to 1 billion cardiomyocytes die. The heart has a limited ability to repair itself, so being able to supply large numbers of potentially patient-matched cardiomyocytes could help."

"These cells will have many applications," says Xiaojun Lian, a UW-Madison graduate student and the lead author of the new study. The beating cells made using the technique he devised have, so far, been maintained in culture in the lab for six months and remain as viable and stable as the day they were created.

Lian and his colleagues found that manipulating a major signaling pathway known as Wnt -- turning it on and off at prescribed points in time using just two off-the-shelf small molecule chemicals -- is enough to efficiently direct stem cell differentiation to cardiomyocytes.

"The fact that turning on and then off one master signaling pathway in the cells can orchestrate the complex developmental dance completely is a remarkable finding as there are many other signaling pathways and molecules involved," says Kamp.

"The biggest advantage of our method is that it uses small molecule chemicals to regulate biological signals," says Palecek. "It is completely defined, and therefore more reproducible. And the small molecules are much less expensive than protein growth factors."


University of Wisconsin-Madison
Proceedings of the National Academy of Sciences
National Institutes of Health
National Science Foundation
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