Predicting the fate of personalized cells next step toward new therapies

May 19, 2011
Earliest cells that form the liver (blue) emerging from progenitor cells (yellow) in the early embryo (green). Credit: Ken Zaret, PhD, Perelman School of Medicine at the University of Pennsylvania

Discovering the step-by-step details of the path embryonic cells take to develop into their final tissue type is the clinical goal of many stem cell biologists. To that end, Kenneth S. Zaret, PhD, professor of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, and associate director of the Penn Institute for Regenerative Medicine, and Cheng-Ran Xu, PhD, a postdoctoral researcher in the Zaret laboratory, looked at immature cells called progenitors and found a way to potentially predict their fate. They base this on how the protein spools around which DNA winds -- called histones -- are marked by other proteins. This study appeared this week in Science.

In the past, researchers grew and waited to see what they differentiated into. Now, they aim to use this marker system, outside of a cell's DNA and genes, to predict the eventual fate. This extra-DNA system of gene expression control is called epigenetics.

"We were surprised that there's a difference in the epigenetic marks in the process for versus pancreas before the 'decision' is made." says Zaret. "This suggests that we could manipulate the marks to influence fate or look at marks to better guess the fate of cells early in the differentiation process."

"How cells become committed to particular fates is a fundamental question in developmental biology," said Susan Haynes, PhD, program director in the Division of Genetics and Developmental Biology at the National Institutes of Health, which funds this line of research. "This work provides important new insights into the early steps of this process and suggests new approaches for controlling stem-cell fate in regenerative medicine therapies."

A Guiding Path

How the developing embryo starts to apportion different functions to different cell types is a key question for developmental biology and regenerative medicine. Guidance along the correct path is provided by regulatory proteins that attach to chromosomes, marking part of the genome to be turned on or off. But first the two meters of tightly coiled DNA inside the nucleus of every cell must be loosened a bit. Regulatory proteins help with this, exposing a small domain near the target gene.

Chemical signals from neighboring cells in the embryo tell early progenitor cells to activate genes encoding proteins. These, in turn, guide the cells to become liver or pancreas cells, in the case of Zaret's work. Over several years, his lab has unveiled a network of the common signals in the mouse embryo that govern development of these specific cell types.

Zaret likens the complexity of this system to the 26-letter alphabet being able to encode Shakespeare or a menu at a restaurant. Many investigators are now trying to broadly reprogram cells into desired cell fates for potential therapeutic uses.

The researchers had previously shown that a particular growth factor that attaches to the cell surface, gives a specific chemical signal for cell-type fate, promoting development along the liver-cell path and suppressing development along the pancreas-cell path. Liver and pancreas cells originate from a common progenitor cell type.

Zaret's group figured out which enzymes -- called histone acetyl transferases or methyl transferases (that add methyl groups or acetyl groups to ) are relevant to the pancreas arm of the liver-pancreas fate decision. They used mice in which they knocked out the function for one enzyme type versus the other to induce the development of fewer liver cells and more pancreas cells.

The transferases mark genes for liver and pancreas fates differently before a cell moves into the next intermediate type along the way to becoming a mature liver or pancreas cell.

Investigators want to make embryonic stem cells for liver or pancreatic beta cells for therapies and research. To do this, they mimic the embryonic developmental steps to proceed from an embryonic stem cell to a mature cell, but have no way of knowing if they are on the right track. The hope is that the findings from this study can be applied to assess the epigenetic state of intermediate progenitor cells.

"By better understanding how a cell is normally programmed we will eventually be able to properly reprogram other cells," notes Zaret. In the near term, the team also aims to generate liver and pancreas cells for research and to screen drugs that repair defects or facilitate cell growth.

With regenerated , researchers hope to one day fill the acute shortage in pancreatic and liver tissue available for transplantation in cases of type I diabetes and acute liver failure.

Explore further: Microbes provide insights into evolution of human language

Related Stories

Cells derived from different stem cells: Same or different?

May 02, 2011

There are two types of stem cell considered promising sources of cells for regenerative therapies: ES and iPS cells. Recent data indicate these cells are molecularly different, raising the possibility that cells derived from ...

Stem cells crucial to diabetes cure in mice

Mar 16, 2009

More than five years ago, Dr. Lawrence C.B. Chan and colleagues in his Baylor College of Medicine laboratory cured mice with type 1 diabetes by using a gene to induce liver cells to make insulin.

Recommended for you

Cell division speed influences gene architecture

Apr 23, 2014

Speed-reading is a technique used to read quickly. It involves visual searching for clues to meaning and skipping non-essential words and/ or sentences. Similarly to humans, biological systems are sometimes ...

Secret life of cells revealed with new technique

Apr 23, 2014

(Phys.org) —A new technique that allows researchers to conduct experiments more rapidly and accurately is giving insights into the workings of proteins important in heart and muscle diseases.

In the 'slime jungle' height matters

Apr 23, 2014

(Phys.org) —In communities of microbes, akin to 'slime jungles', cells evolve not just to grow faster than their rivals but also to push themselves to the surface of colonies where they gain the best access ...

Queuing theory helps physicist understand protein recycling

Apr 22, 2014

We've all waited in line and most of us have gotten stuck in a check-out line longer than we would like. For Will Mather, assistant professor of physics and an instructor with the College of Science's Integrated Science Curriculum, ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

neiorah
not rated yet May 19, 2011
Maybe soon they will be able to grow another liver from a persons own cells for no chance of rejection. Once they figure all this out, who knows we might be able to live indefinitely and in good health.

More news stories

New breast cancer imaging method promising

The new PAMmography method for imaging breast cancer developed by the University of Twente's MIRA research institute and the Medisch Spectrum Twente hospital appears to be a promising new method that could ...

Research proves nanobubbles are superstable

The intense research interest in surface nanobubbles arises from their potential applications in microfluidics and the scientific challenge for controlling their fundamental physical properties. One of the ...

Using antineutrinos to monitor nuclear reactors

When monitoring nuclear reactors, the International Atomic Energy Agency has to rely on input given by the operators. In the future, antineutrino detectors may provide an additional option for monitoring. ...