Cells derived from embryonic stem cells, iPS cells appear immature

A trend over the past few years has been comparing embryonic stem cells, adult stem cells and reprogrammed adult cells (also known as iPS cells) to each other and to other cell types. The goal is to understand what the cells are, exactly, and and how they differ from each other. Eventually this information could help researchers learn which type of cell will be most effective for developing therapies, understanding diseases or drug screening.

A group of CIRM grantees at UCLA has published the latest in the unfolding story of stem cell comparisons. In their case, they didn't compare the stem cells themselves. Instead, they matured embryonic stem cells and iPS cells into the cells that eventually form neurons, cells that eventually form skin, and cells that eventually form liver. These so-called progenitor cells also exist in adult humans, where they lurk in tissues waiting to be needed to repair damage.

The scientists compared the progenitor cells to each other and to equivalent cells taken from adult tissue as well as to developing tissues. What they found is that the progenitors for nerves, skin and liver that came from embryonic or iPS cells had a lot in common with each other and with developing tissues. However, they had much less in common with their counterparts taken from adult tissues.

A press release from UCLA quotes William Lowry, who was senior author on the paper, which appeared in Cell Research.

“What we found, looking at gene expression, was that the cells we derived were similar to cells found in early fetal development and were functionally much more immature than cells taken from human tissue. This finding may lead to exciting new ways to study early human development, but it also may present a challenge for transplantation, because the cells you end up with are not something that’s indicative of a cell you’d find in an adult or even in a newborn baby.”

The release goes on to quote first author Michaela Patterson:

“One important reason to do this is to ensure that the cells we are creating in the Petri dish and potentially using for transplantation are truly analogous to the cells originally found in humans,” said Michaela Patterson, first author of the study and a graduate student researcher. “Ideally, they should be a similar as possible.”

…

“The roles these cells play in the fetus and the adult are inherently different,” she said. “It may be that the progeny, if transplanted into a human, would mature to the same levels as those found in the adult liver. We don’t know.”

This is the first paper we've seen comparing progenitor cells to adult or developing tissues. As with all first steps, we'll likely see more papers over the next few years refining and expanding on this team's findings and clarifying what these findings mean in terms of transplantation.

CIRM Funding: William Lowry (RS1-00259-1), Michaela Patterson (T1-00005)
Cell Research, August 16, 2011

A.A.

iPS developments - faster creation, but questions raised

Two pieces of news came out today about reprogrammed iPS cells — one showing a new way of making them and the other suggesting that they may not be all they’re cracked up to be.

First, the new technique. A team at Sanford-Burnham Medical Research Institute in La Jolla figured out a way of removing barriers to reprogramming, in which skin or other adult cells are reprogrammed back to an embryonic-like state. Most techniques for reprogramming involving adding DNA or other factors to push the cells back in developmental time. But the process isn’t very efficient. This team identified two barriers to reprogramming and removed them using small inhibitory molecules called miRNAs.

The Sanford-Burnham press release quotes CIRM grantee Evan Snyder, director of Sanford-Burnham’s Stem Cells and Regenerative Biology program:

“Up until now, cellular differentiation and de-differentiation has focused principally on the expression of genes; this work indicates that the strategic non-expression of genes may be equally important. The work has demonstrated that miRNAs do function in the reprogramming process and that the generation of iPSCs can be greatly enhanced by modulating miRNA action. In addition to helping us generate better tools for the stem cell field, such findings inevitably facilitate our understanding of normal and abnormal stem cell behavior during development and in disease states.”

Ironically, on the same day the authors published the fruits of many years of labor, the news cycle delivered a blow. Researchers down the road at The Salk Institute for Biological Studies published yet another report showing critical differences between iPS and embryonic stem cells. There’s been a steady drumbeat over the past year of studies pointing out that iPS cells might not exactly mimic embryonic stem cells, and for that reason might not be ideal replacements in therapies.

William Lowry, a CIRM grantee at UCLA, is quoted in a Nature news story about the finding:

"The problem is that we don't know if any of these differences are going to be consequential."

Whether these differences between iPS and embryonic stem cells will turn out to be insurmountable in terms of future therapies is unknown. What is clear is that scientists have many hours in the lab ahead of them before we understand which cells are the safest and most effective for eventual therapies.

- A.A.

iPS cells from women create model for muscular dystrophy, X-linked diseases

Reprogrammed skin cells showing inactivated X in red

CIRM grantees at the University of California, Los Angeles have uncovered a feature of reprogrammed iPS cells that make them uniquely excellent for understanding diseases that arise from mutations on the X chromosome.

First some background. Men inherit an X chromosome from their mother, which contains many thousands of genes, and a Y from the father, which does little except confer manhood. Women inherit one X chromosome from each parent. Those female cells overcome their genetic overabundance by shutting down, at random, one of the two X chromosomes, putting the cells at genetic par with male cells.

But the two aren’t really equal. If men inherit a mutation on an X chromosome, it is present in every cell of the body and can cause muscular dystrophy, Rett Syndrome, color-blindness and other disorders. Women who inherit a mutation on an X chromosome from one parent will only show that mutation in half their cells. The other half of the body's cells, with the non-mutated chromosome active, can generally compensate.

So what does this have to do with reprogrammed cells and disease modeling? It turns out that the process of reprogramming skin cells into embryonic-like induced pluripotent stem cells doesn’t overturn the inactivated X. Reprogramming cells from a woman’s skin sample will produce two distinct types of iPS cell lines; half with one X active, and half of with the other X active. If one of those two chromosomes carries a mutation, say, for muscular dystrophy, some of those iPS lines will also display that mutation.

In a press release from UCLA, senior author Kathrin Plath said:

“This non-random pattern of X chromosome inactivation found in iPS cell lines has critical implications for clinical applications and disease modeling and could be exploited for a unique form of gene therapy for X-linked diseases.”

In a publication in Cell Stem Cell, Plath and her colleagues report that they created iPS cell lines from a woman who had inherited one X chromosome carrying a mutation that can cause muscular dystrophy. The other X chromosome had a normal copy of the gene. Scientists can now mature both groups of cells into skeletal muscle and compare the resulting tissue as a way of understanding—and perhaps one day treating—the devastating disease.

Cell Stem Cell: September 3, 2010
CIRM funding: Sean Sherman (TG2-01169), Kathrin Plath (RN1-00564), William Lowry (RS1-00259), Jerome Zack. (RL1-00681)

Genetic differences found between adult cell and embryonic-derived stem cells

Researchers at the University of California, Los Angeles have found genetic differences that distinguish induced pluripotent stem (iPS) cells from embryonic stem cells. These differences diminish over time, but never disappear entirely. iPS cells are created when adult cells, such as those from the skin, are reprogrammed to look and behave like embryonic stem cells. But until now, scientists didn’t know if the two types of stem cells were actually identical at a molecular level. This latest research shows that iPS and embryonic stem cells differ in which genes they have turned on or off. All early iPS cells share these genetic traits, regardless of what animal they come from, the type of adult cells the iPS cells start as, or what method was used to reprogram those adult cells. However, later cultures of iPS cells show that most, but not all, of these differences disappear over time, making later cultures of iPS cells more similar to embryonic stem cells. If scientists want to use iPS cells in medical therapies, this research will give them a better idea of how similar they are to embryonic stem cells.

Cell Stem Cell: July 2, 2009
CIRM funding: Mike Teitell (RS1-00313), Kathrin Plath (RN1-00564-1), William Lowry (RS1-00259-1, RL1-00681-1)

Related Information: Press Release, University of California, Los Angeles

iPS Cells Mature into Functional Motor Neurons

Researchers at the University of California, Los Angeles have matured induced pluripotent stem (iPS) cells into what appear to be normal motor neurons. This work shows that iPS cells can mature into cells that appear similar to those derived from human embryonic stem cells – a finding that has important implications for people hoping to create new therapies based on iPS cells. These cells are created by reprogramming adult cells back into a pluripotent state that resembles embryonic stem cells. One question has been whether these reprogrammed cells have the same capacity as embryonic stem cells to turn into mature, functioning cell types. This work shows that, at least for motor neurons, iPS and embryonic stem cells have the same capacity to form mature cells. Scientists can study these motor neurons in the lab to learn about – and find cures for – diseases such as amyotrophic lateral sclerosis (Lou Gehrig’s Disease), spinal muscle atrophy or spinal cord injury.

Stem Cells:February 23, 2009 (online publication)
CIRM funding: William Lowry (RS1-00259)

Related Information: Broad Stem Cell Research Center, Lowry lab page