Fresh hope on stem cells use to regenerate human organs

December 29, 2013 9:37 PM

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THREE new but independent studies have raised hope for the use of stem cells to regenerate human organs in laboratories.

Researchers have demonstrated a novel technique that could resolve a snag in stem cell research for application in regenerative medicine- a strategy for reprogramming cells in vivo to act like stem cells that forgoes the risk of causing tumours.

The study was published in JoVE, the Journal of Visualised Experiments, by the principal investigator of the Nanomedicine Lab at the University of Manchester, United Kingdom (UK), Dr. Kostas Kostarelos.

Kostarelos said that he and his colleagues had discovered a safe approach to reprogramming somatic cells (which constitute most of the cells in the body) into induced pluripotent stem (iPS) cells. Research in this field has been embraced as an alternative to the controversial use of embryonic stem cells.

He explained: “We have induced somatic cells within the liver of adult mice to transiently behave as pluripotent stem cells. This was done by transfer of four specific genes, previously described by the Nobel-prize winning Shinya Yamanaka, without the use of viruses but simply plasmid DNA (a small circular, double-stranded piece of DNA used for manipulating gene expression in a cell).”

The technique comes as an alternative to Dr. Shinya Yamanaka’s reprogramming methods, which won him the Nobel prize in 2012. Dr. Yamanaka’s approach involved reprogramming somatic cells in vitro by introducing four genes through the use of a virus. While promising, the use of this method has been limited. As Kostarelos’s article states, “One of the central dogmas of this emerging field is that in vivo implantation of [these stem] cells will lead to their uncontrolled differentiation and the formation of a tumour-like mass.”

Kostarelos and his team have determined that their technique does not share the risk of uncontrolled stem cell growth into tumors as seen in in vitro, viral-based methods. “(This is the) only experimental technique to report the in vivo reprogramming of adult somatic cells to pluripotency using non-viral, transient, rapid and safe methods,” Kostarelos said.

The Nanomedicine Lab’s approach involves injecting large volumes of plasmid DNA to reprogram cells. However, because plasmid DNA is short-lived in this scenario, the risk of uncontrolled growth is reduced.

The research group chose to publish their technique with JoVE as a means to emphasize the novelty, uniqueness and simplicity of their procedure. Along with their article, a demonstration of their technique has been published as a peer-reviewed video to ensure the proper replication of this technique by other researchers in the field.

Meanwhile, researchers in the Cedars-Sinai Regenerative Medicine Institute have designed and tested a novel, minute-long procedure to prepare human amniotic membrane for use as a scaffold for specialized stem cells that may be used to treat some corneal diseases. This membrane serves as a foundation that supports the growth of stem cells in order to graft them onto the cornea.

This new method, explained in a paper published this month in the journal PLOS ONE, may accelerate research and clinical applications for stem cell corneal transplantation.

Corneal blindness affects more than eight million people worldwide. Among other causes, corneal blindness can be the outcome of corneal stem cell deficiency, a disease usually resulting from genetic defects or injury to the eye- such as burns, infection or chronic inflammation- that can lead to vision loss. A feasible treatment to rectify vision loss for such patients is corneal stem cell transplantation, either as a biopsy from another eye or by transplanting cultured stem cells, although this promising approach is not yet fully standardised.

An approved biological foundation for cultured stem cells is the human amniotic membrane, a thin but sturdy film that separates the fetus from the placenta. For the best growth of stem cells, amniotic cells need to be removed by chemical agents. The existing methods for removing these cells from this membrane are not standardised, leave behind amniotic cells and may cause unwanted loss of some of the membrane components.

The amniotic cell removal method created at Cedars-Sinai takes less than one minute and ensures virtually complete amniotic cell removal and preservation of amniotic membrane components, and also supports the overall growth of various stem and tissue cells.

“We believe that this straightforward and relatively fast procedure would allow easier standardisation of amniotic membrane as a valuable stem cell support and improve the current standard of care in corneal stem cell transplantation,” said lead author Alexander Ljubimov, PhD, director of the Eye Programme at the Cedars-Sinai Regenerative Medicine Institute. “This new method may provide a better method for researchers, transplant corneal surgeons and manufacturing companies alike.”

Mehrnoosh Saghizadeh Ghiam, PhD, a research scientist in the Regenerative Medicine Institute’s Eye Programme, assistant professor in the Department of Biomedical Sciences and first author of the study, commented on the potential of the new method.

“The amniotic membrane has many beneficial properties and provides an attractive framework to grow tissue and stem cells for regenerative medicine transplantations, especially in replacing missing stem cells in the cornea,” said Saghizadeh. “Our method for preparing this scaffold for cell expansion is and may streamline clinical applications of cell therapies.”

Meanwhile, scientists have created miniature 3D kidney structures from human stem cells with the aim of providing just that.

Investigators from the Salk Institute for Biological Studies in California say the mini-kidney structures could open new avenues for studying the development of kidney disease and lead to the creation of new drugs that target the condition.

The researchers note that although scientists had previously created precursors of kidney cells using human stem cells this year, the team at Salk is the first to create 3D cellular structures that are similar to those found in human kidneys.

How were the 3D kidney structures created? Scientists used mouse embryonic kidney cells (red) to ‘coax’ human stem cells to turn into early-stage uretic buds - early structures of the human kidney.

The researchers explain that the 3D structures, the details of which are published in the journal Nature Cell Biology, demonstrate that pluripotent stem cells (PSCs) can be changed into cells similar to those found in the uretic bud - a structure found in the early development of kidneys.

The investigators say they were able to do this using both human embryonic stem cells and induced pluripotent stem cells (iPSCs) - human cells from the skin that have been “reprogrammed into their pluripotent state.”

The research team created iPSCs that showed pluripotent properties and were able to “differentiate” into mesoderm - a germ layer from which the kidneys develop.

The scientists used growth factors known to play a part in the natural development of human kidneys in order to culture both iPSCs and embryonic stem cells.

They explain that the combination of signals from these growth factors, which they describe as molecules that “guide the differentiation of stem cells into specific tissues,” were enough to “commit” the cells toward progenitors that demonstrated characteristics of kidney cells in four days.

By culturing these progenitor cells with kidney cells from mice, the researchers were able to create organ structures similar to structures found in the uretic bud.

The researchers say this demonstrates that the mouse cells were able to provide the “appropriate developmental cues,” which allowed the human stem cells to turn into 3D kidney structures.

Explaining their findings further, senior study author Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, says: “Attempts to differentiate human stem cells into renal cells have had limited success. We have developed a simple and efficient method that allows for the differentiation of human stem cells into well-organized 3D structures of the ureteric bud, which later develops into the collecting duct system.”

The investigators tested their method on iPSCs from a patient who was clinically diagnosed with polycystic kidney disease (PKD) and discovered that they were able to create 3D kidney structures from these patient-derived cells.

PKD is a genetic form of kidney disease that is characterized by multiple cysts filled with fluid. The researchers explain that because of the symptoms of this disease, gene-based or antibody-based strategies are “not realistic” for treating the condition.

Therefore, they note that the 3D structures could be used in the testing of drugs to combat PKD and other diseases of the kidney.

“Our differentiation strategies represent the cornerstone of disease modeling and drug discovery studies,” says lead study author Ignacio Sancho-Martinez.

“Our observations will help guide future studies on the precise cellular implications that PKD might play in the context of kidney development.”

Earlier this year, Medical News Today reported on the creation of mini-brains grown from stem cells.


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