Minimizing the cellular contaminants that plague the differentiation of pluripotent stem cells

June 18, 2014
Minimizing the cellular contaminants that plague the differentiation of pluripotent stem cells
Liver cells derived from human pluripotent stem cells. The colors red and green mark the expression of liver genes in the cells. Credit: A*STAR Genome Institute of Singapore

Embryonic stem cells (ESCs) have the potential to form more than 200 distinct cell types in the human body. Although ESCs can differentiate into any specialized tissue, scientists are still unsure of how to coax these pluripotent cells to reliably form a desired cell type without producing a mix of contaminating cell lineages.

A research team led by Bing Lim from the A*STAR Genome Institute of Singapore has now developed a new method for directing ESCs into highly pure populations of or pancreas cells. These untainted populations of organ-specific cells could form the basis of future therapies or be used as platforms upon which to screen drugs.

"Heterogeneous mixtures of cell types are unsuitable for transplantation or other therapeutic purposes," says Kyle Loh, a previous member of Lim's lab now based at the Stanford University School of Medicine in the United States. "We can precisely differentiate into a pure population of a given lineage of interest," he explains.

Lay Teng Ang of the liver research program in Lim's lab sought a way to guide human ESCs to differentiate reliably into endoderm—the cell type that gives rise to organs including the lungs, liver and intestines. To do this, Ang systematically perturbed developmental signals at four consecutive steps of endoderm formation, searching for molecules that could produce a single, desired cell type as well as block the induction of unwanted alternatives. Along the way, the researchers generated what Lim calls "a roadmap for endoderm differentiation."

Their strategy showed that a variety of growth factors and signaling proteins initially help transform ESCs into endoderm progenitor cells. However, the researchers had to inhibit these same molecules within 24 hours to prevent the cells from turning into another tissue type known as mesoderm.

Knowledge of this timing and the downstream signaling dynamics eventually allowed Lim's team to differentiate the ESCs into pure populations of liver and , while excluding other lineages at each developmental branch point. The researchers also noted the endodermal enhancers existed in a surprising diversity of 'pre-enhancer' states as uncommitted cells prior to activation: they also documented the 'permissive' chromatin marks that provide ESCs with their flexible developmental capacity.

"We first needed to understand the signals that control stem —and thus what controls lineage splitting," Loh says. "Then we could unilaterally repress differentiation of ESCs towards other and instead drive stem cells exclusively toward a uniform population of desired stem ."

Explore further: Scientists succeed in manipulating stem cells into liver and pancreas precursor cells

More information: Loh, K. M., Ang, L. T., Zhang, J., Kumar, V., Ang, J. et al. "Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations." Cell Stem Cell 14, 237–252 (2014). dx.doi.org/10.1016/j.stem.2013.12.007

Related Stories

Study reveals how to better master stem cells' fate

October 24, 2013

(Phys.org) —USC scientist Qi-Long Ying and a team of researchers have long been searching for biotech's version of the fountain of youth—ways to encourage embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) to ...

Recommended for you

New discovery challenges long-held evolutionary theory

October 19, 2017

Monash scientists involved in one of the world's longest evolution experiments have debunked an established theory with a study that provides a 'high-resolution' view of the molecular details of adaptation.

Water striders illustrate evolutionary processes

October 19, 2017

How do new species arise and diversify in nature? Natural selection offers an explanation, but the genetic and environmental conditions behind this mechanism are still poorly understood. A team led by Abderrahman Khila at ...

Gene editing in the brain gets a major upgrade

October 19, 2017

Genome editing technologies have revolutionized biomedical science, providing a fast and easy way to modify genes. However, the technique allowing scientists to carryout the most precise edits, doesn't work in cells that ...

Gut bacteria from wild mice boost health in lab mice

October 19, 2017

Laboratory mice that are given the gut bacteria of wild mice can survive a deadly flu virus infection and fight colorectal cancer dramatically better than laboratory mice with their own gut bacteria, researchers report October ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.