Using bone marrow stem cells to repair a trachea

Physicians at London’s Great Ormond Street Hospital for Children, in collaboration with researchers from Italy, have used a boy’s own stem cells to rebuild his windpipe. To do this, they removed the cells from a donor trachea so that only the collagen skeleton of the trachea was left. Then they collected bone marrow stem cells from the patient, and pasted them throughout the tracheal skeleton. Because these cells were taken from the patient, their chances of being rejected by the immune system are quite low. After the nine-hour surgery, the boy is in good health.

Martin J. Elliot, director of tracheal services of Great Ormond Street and the developers of Europe’s first specialized tracheal surgery service for children said, “The child is extremely well. He’s breathing completely for himself and speaking, and he says it’s easier for him to breathe than it has been for many years.” The physicians hoped that over the next few months the stem cells will grow throughout the trachea and transform into tracheal epithelial cells. This procedure could be an amazing advance in regenerative medicine.

Martin Birchall, a collaborator on this work said, “This procedure is different in a number of ways, and we believe it’s a real milestone.” He continued, “It is the first time a child has received stem cell organ treatment, and it’s the longest airway that has ever been replaced.”
This particular patient was born with long segment tracheal stenosis (narrowing). This life-threatening disease can greatly inhibit the ability to breathe.

After unsuccessful trials, this research group contacted Paolo Macchiarini from Careggi University Hospital in Florence, Italy. Macchiarini directed the first transplant organ surgery with stem cells on a 30-year-old patient who received a new portion of trachea after her own was impaired from tuberculosis. Macchiarini had the bright idea to use the boy’s own stem cells to restore his trachea. However, this procedure aspired to replace the entire trachea instead of a small portion of the trachea. While the initial results are very interesting, additional research is necessary to determine if the procedure works over long-term. If successful, it could lead researchers to attempt to transplant other engineered organs such as the larynx or esophagus.

Stem Cells Used to Model Infant Birth Defect

One of the powerful uses of stem cells is their ability to model diseases. One recent report shows how stem cells can provide such a use.

Do you remember those strawberry-like birthmarks you have? They’re called hemangiomas. For the most part they are quite harmless. However, a stark minority of hemangiomas (~10%) can cause trouble if they occur within particular tissues. Hemangiomas consist of knots of blood vessels and if they form in the eyes, they can produce vision trouble, and if they form in lungs, they can cause circulation defects in the lungs.  Worse still, hemangiomas can continue growing and become tumors.

Traditionally, treatment of damaging hemangiomas has been with steroid drugs. There are problems with such treatments though. Steroids have many undesirable side effects, and they don’t always work. Even more troubling is the fact that the means by which steroids work are a complete mystery.

Now, workers at Children’s Hospital Boston recently shown that hemangiomas that form during development come from stem cells. Additionally, by growing these stem cells in the laboratory, scientists have been able to use them to understand how steroids treat hemangiomas (New England Journal of Medicine, March 18).

Hemangiomas are tangles of blood vessels that originate from specialized stem cells called hemangioma stem cells.  These cells can overgrow and produce little knobs of tissue.  Steroids work by shutting down the ability of hemangioma stem cells to grow.  In order to grow, hemangioma stem cells make a growth factor called vascular endothelial growth factor-A (VEGF-A).  This self-made growth factor increases the growth of the hemangioma stem cells, and steroids shut down the production of VEGF-A, thus inhibiting their growth.

Why is this exciting?  It turns out that VEGF-A is rather well understood, and there are other tools for inhibiting VEGF-A signaling.  This means that much safer drugs are available to treat hemangiomas.  Furthermore, not all hemangiomas respond to steroids (~30%).  This work suggests that hemangioma stem cells that form the hemangiomas may harbor mutations that causes them to overgrow and form knots of blood vessels.  Some of these mutant stem cells respond to steroids and some do not.  Some of the screening methods applied in this study may tell pathologists if steroid treatment will help or not.

By using stem cells from the tumor and manipulating them in the laboratory, scientists were able to learn basic things about common tumors and often manifest themselves as birthmarks.  This is hopefully only one of many different kinds of diseases that will be modeled through experiments on stem cells.

Mouse models aren’t good enough for human stem cell research

Mice are a common model system for clinical research. This also applies to embryonic stem cells, since mouse embryonic stem cells (mESCs) grow and differentiate like human embryonic stem cells (hESCs). However, further work has shown that there are many molecular differences between mESCs and hESCs. This is the case even though complete sequences of mouse and human genomes have revealed that 99% of mouse genes encode for corresponding genes in humans. Now a paper from the Max Planck Institute indicates that mouse models may not be very good representatives of the developmental behaviors of hESCs.

This researcher group, led by Hans Schöler, found that mouse epiblast cells, which were believed to be the closest animal-based model to hESCs, behave differently in the presence of the growth factor FGF than their human counterparts. “Our latest study demonstrates that animal model systems are inadequate for a great many tests,” Schöler said in a press release.

There has been a fair amount of curiosity among stem cell scientists to determine how accurately findings from mESCs parallel hESCs. hESCs and mESCs share several characteristics: they are both pluripotent, and have an active Oct4 gene that serves as a transcription factor.

However, hESCs and mESCs have some distinct differences. Signaling pathways used to differentiate mESCs into liver, nerve, or muscles cells produce either no effect or completely different effects in hESCs.

In 2007, scientists seeking a better animal model for human tissues discovered a new type of pluripotent cell in mice.  They called this cell “mouse epiblast stem cells,” or “EpiSCs.”  EpiSCs are pluripotent, but they are unlike mESCs in that they are not made from early pre-implantation embryos, but from a later stage of embryonic development, when the embryo has already implanted into the uterus.  Although EpiSCs are more advanced in their development than a typical mESC, they share some important similarities with hESCs than mESCs.  For example, both EpiSCs and hESCs can be grown and preserved in their pluripotent state with the addition of the growth hormones FGF2 and Activin A.  “EpiSCs from mice are therefore more-or-less equated with hESCs in the general scientific discussion,” said lead author Boris Greber.

To determine how accurately EpiSCs mimicked hESCs, Greber and his collaborator Schöler and their co-workers evaluated how these two cell types behaved in the presence of different growth factors and inhibitors.  Two growth factors called “Activin” and “FGF” are both active in EpiSCs and hESCs.  Activin promotes self-renewal in both EpiSCs and hESCs by communicating with a signal transduction pathway that uses SMAD2/3 and a protein called Nanog.

FGF, however, was another story.  Even though Activin works similarly in both cell types, FGF works with Activin to signal SMAD2/3 and Nanog to promote self-renewal in hESCs.  However, in EpiSCs FGF does not signal SMAD2/3 and Nanog, but signals the gene Klf2, which activates pluripotency. Klf2 expression in EpiSCs keeps the cells in their pluripotent state, and inhibits differentiation into neural-like tissue, and prevent EpiSCs from reverting to an earlier stage of embryonic development.  Because FGF growth hormone has different effects in EpiSCs and hESCs, EpiSC differentiation probably does not accurately represent the differentiation process in hESCs.

This paper argues for the centrality of hESCs in future stem cell studies.  Reprogramming technologies and mechanisms for differentiating stem cells still have a long way to go before they are fully understood, since there are probably molecular differences between induced pluripotent stem cells and hESCs that are not apparent from simply looking at them.  “We will still need hESCs as the gold standard against which to compare everything else,” said Schöler.

Schöler also said that testing in somatic human cells would not replace tests in embryonic cells because there is still very little understanding about the signaling pathways that control the differences between the two cell types. “The recent successes in reprogramming mature human somatic cells make it look as though tests using hESCs are nowadays redundant,” said Schöler. “But appearances are deceptive.”