Cells derived from pluripotent stem cells are developmentally immature

Aug 17, 2011

Stem cell researchers at UCLA have discovered that three types of cells derived from human embryonic stem cells and induced pluripotent stem cells are similar to each other, but are much more developmentally immature than previously thought when compared to those same cell types taken directly from human tissue.

The researchers, from the Eli and Edythe Broad Center of Regenerative Medicine and at UCLA, found that the progeny of the human and induced pluripotent stem cells (iPS) were more similar to cells found within the first two months of than anything later. This could have implications both clinically and for disease modeling, said William Lowry, senior author of the study and an assistant professor of molecular, cell and in the Life Sciences.

The two-year study was published today in the peer-reviewed journal Cell Research.

"Once we found that the human embryonic stem cell- and the iPS-derived progeny were similar, we wanted to understand how similar the progeny were to the same cells taken directly from ," Lowry said. "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 ."

There might also be challenges in disease modeling, unless you're modeling diseases that occur within the first two months of development, Lowry said.

Employing the most commonly used methods for deriving cells from embryonic stem cells and iPS cells, Lowry and his team differentiated these human pluripotent stem cells into , which create neurons and glia, hepatocytes, the main tissue found in the liver, and fibroblasts, common to the skin. They selected those cell types because they are easy to identify and are among the most commonly differentiated cells made from pluripotent stem cells. They also represent cell types found in the three germ layers, the endoderm, mesoderm and ectoderm, where the first cell fate decisions are made, Lowry said.

The progeny of the human pluripotent stem cells were compared to each other using their gene expression patterns, functionality and appearance. There was essentially little or no difference between them, Lowry said. Then the work began to compare them to equivalent cell types found in humans.

"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."

What the team found was that while the progeny were alike, they bore striking differences from the same cells found in humans when analyzing their gene expression. A significant number of genes, about 100, were differentially expressed in the cell types made from pluripotent stem cells, Lowry said.

About half of those differentially expressed genes are normally thought to be strictly expressed in pluripotent stem cells, which have the potential to differentiate into any cell of the three germ layers. Those genes had not been turned off even after the cell had differentiated into either a neural progenitor cell, hepatocyte or a fibroblast, Patterson said.

"Previously, we assumed that all pluripotency genes get shut off right away, after the fetus begins developing," Patterson said. "We found that this is not the case, and in fact some of these genes remain expressed."

The differences in gene expression could be problematic, Lowry said, because some of these same differentially expressed genes in the progeny are genes that are expressed during cancer development. Also worrisome was their developmental maturity – would they work correctly when transplanted into humans? As part of their study, the team left the differentiating cells in culture about a month longer to see if they would further mature, and there was some modest but statistically significant maturation. However, genetic discrepancies remained.

These discrepancies could be critical, Patterson said, particularly in the hepatocytes. During fetal development, these cells express proteins that aid the metabolism of the fetus, a role they don't play later in adults.

"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."

The team then compared the progeny to cells from humans that were closer to the progeny's developmental maturity and found that the two types of cells were indeed becoming more similar in and functionality, Lowry said.

The UCLA team is not the first to suggest that the progeny of human pluripotent reflect an early developmental immaturity. However, these data put a more precise window on their developmental age.

Going forward, Lowry and his team are going to study the 100 genes being differentially expressed in the to see if manipulating some or all of them results in the maturation of the cells.

"These findings provide support for the idea that human can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical applications of their derivatives," the study states.

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Provided by University of California - Los Angeles

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Turritopsis
not rated yet Aug 17, 2011
Yes, of course. Embryonic cells are undeveloped (stage zero years) compared has full human potential, cellular division is task differentiating cellular management (cells gain purpose). To show correlation take for example a stem cell and examine progressive cellular appropriation, after 20 years we have a mature adult, with functioning skeletal muscular vascular digestive ingestive reproductive observational psychological (list goes on)... systems and within each system there is subdivisions. Each subdivision is a developmental step. The more steps (time derivative) the higher the maturity level. Stemcells hold research benefits but eventually you realize that only corrected (altered genetically for higher functionality) is the direction to aim for. For instance, when I run I create high cardiovascular demand, should my heart be at a low developmental stage (as in embryonically grown for me extrabodily) it wouldn't be hardened to sustain the stresses I'm putting on it. Stem cell thera
Turritopsis
not rated yet Aug 17, 2011
rapy can only be effective when coupled with correct cellular language. With correct language (DNA coding) no stemcells are required for therapy anyways. By genetic componetry manipulation (rewriting DNA) we can alter developmental stages (dual directionally). Craig Venter has shown that cells can be (not only altered) but constructed from underlying components, but, that art is in its developmental stages, many more hours of thinking need to be placed in there. The problem is the actual synthesizing process. It is difficult working at atomic molecular scales when your equipment is made up of atoms itself.
Turritopsis
not rated yet Aug 17, 2011
Magnetic field manipulation could create only 1 arrangement for the molecules to fit into. This could replace the primitive tools. An electromagnetic field could create a template for the components to occupy. After construction the field is slowly reversed and the cell remains. Precision electronics allow for point access within a patient (radiation therapy is still primitive). The programming is too simple at this time, infinitely high potential is required (finite complexity with growth opportunity in all directions), atomic alteration at distance via electromagnetism (positrons & electrons for dual directionality and infinite workability) and the most important part is the scoping. You need the ability to differentiate between components (know what is what) you don't want to radiate through the body blindly (this causes cancer (genetic mutations)). Requirements are the ability to see and operate on correct components, if you want to work on cells you need to see all the components
Turritopsis
not rated yet Aug 17, 2011
of that cell and you need the ability to change out malfunctioning ones.

Radiation therapy works by attacking all the cells (the weakest of them, usually mutated, die first, only the strong survive).

Telomeres protect genetic information (they hold the DNA strand together). As the ability to hold DNA weakens so does likelyhood of mutation (cancer). When telemores dissapear altogether so do the cells (with no telomeres dna is not held together). If we change the telomere to an artificial system we can control the rate of decay. Telomeres decay at a quick rate (much quicker than I'd like them to). Mission number 1 for humanity should be one of DNA preservation. Artificial DNA control is not as complicated as one would think, it is, however, highly demanding. How many cells are in the human body?
Brendan F
not rated yet Aug 25, 2011
I always kind of thought that differentiating ES cells into specific progeny sounded like a pretty enormous problem. I mean, just because these ES cells have the theoretical ability to differentiate into any kind of cell in vivo (i.e. in tetraploid complementation or teratoma formation)doesn't mean that the in vitro manufacture of specific cell types would be very easy at all. It is certainly not natural, by any means.
re: Turritopsis:
Craig Venter's work, while very impressive, by no means shows how cells can be constructed from underlying components. Venter synthesized a complete bacterial genome, which he used to transform other bacterial cells. He did not synthesize a new cell. As for precision nano-engineering; we need to solve basic biological problems like gene-regulatory networks (i.e. what Lowry is talking about here) before we start worrying about building cells at an atomic level. We don't know nearly enough bio to know what to do with atomic-level engineering right now.