Engineering Organs

Demand almost always surpasses supply, often greatly, when it comes to human organs for patients in need of transplants. This has motivated many researchers to work toward engineering biological tissues and organs (a field called “bioengineering”) suitable for transplants. Stem cells, displaying their wide medical utility, have played a significant role is this quickly expanding field.

In 2008, a significant breakthrough occurred when researchers created the first human organ manufactured using stem cells, and then transplanted it successfully into a patient, 30-year-old Claudia Castillo. Due to a severe tuberculosis infection, Castillo’s left bronchus (which is where the windpipe has branched off to the separate lungs) had become almost entirely collapsed; her breathing was so impaired that she could no longer carry out simple domestic chores.

Castillo’s relatively unique and tragic situation led Dr. Paolo Macchiarini (University of Barcelona, Spain) and his colleagues, after exhausting traditional approaches, to test a novel organ transplant therapy on her, which had previously been successful in mice and pigs. To treat her, they needed to remove and replace her failed bronchus entirely (see a diagram of the entire procedure used here). Normally, replacement of large airway pieces and other organs is a significant problem because the patient must remain on immunosuppressant medications for life to prevent rejection of the new donated tissue, and this can shorten a patient’s lifespan by 10 years or more. However, the risks of immune rejection were overcome by, amazingly, using Castillo’s own stem cells to create the synthetic organ.

To create the replacement bronchus, a donated airway from a cadaver was obtained and treated so that all donor’s cells were removed. The specific piece of donated airway was a segment of trachea. After all connected tissues were removed from it, the trachea segment was extensively treated to remove any cells (to be used in a transplant, all “foreign,” or donor, cells must be removed to prevent immune rejection by the patient). This procedure took more than six weeks, and involved 25 cycles of the trachea being incubated with detergents and enzymes that break down DNA. After this laborious process, only the cartilage of the trachea remained, leaving a hollow, bleached tube.

This blanched trachea, now devoid of any donor tissues and cells, acted as the perfect scaffold for Castillo’s own cells to be grown on. Two different kinds of cells were taken from Castillo and grown on the trachea: epithelial cells (cells that cover the inside and outside of organs) and chondrocytes (cartilage cells). The epithelial cells were taken from the moist tissue lining (mucosa) of Castillo’s healthy bronchus and were coaxed to grow on the inside of the donor trachea. Obtaining the chondrocytes was a bit trickier; the researchers created the chondrocytes from a population of stem cells in Castillo’s body. From a sample of Castillo’s bone marrow, the researchers isolated mesenchymal stem cells, and then turned these stem cells into chondrocytes in just three days (using an established procedure of exposing the cells to specific molecular factors). These chondrocytes were grown all over the outside of the trachea.

The epithelial cells, on the inside of the trachea, and the chondrocytes, on the outside of the trachea, were both grown in their own different environments (exposed to different growth factors and conditions) that mimicked what they would encounter in the human body. This was done in a “bioreactor,” a box where the inside and outside of the trachea were exposed only to their two separate environments. The cells were grown on the trachea in the bioreactor for four days, at which point the researchers had created, or bioengineered, a human airway lacking any synthetic parts and populated by Castillo’s own cells.

Once the bioengineered trachea was ready, the near-collapsed portion of Castillo’s left bronchus was removed and replaced by the trachea, now acting as a segment of bronchus. A month after the transplant, the trachea was indistinguishable from Castillo’s normal right bronchus and the surrounding bronchus tissue. The transplanted airway displayed completely normal function. In 2009, a year later, it was reported that the graft and patient are still doing fine. Castillo is not only able to do daily chores, but even to dance!

In late March of this year, this same strategy was successfully used in a 10-year-old boy. Dr. Macchiarini, who is an honorary professor at the University College London (UCL), worked with doctors and researchers at UCL, the Great Ormond Street Hospital for Children (GOSH) in London, the Careggi University Hospital in Florence, and others, to perform the transplant. The boy had a rare condition called long segment congenital tracheal stenosis, which resulted in the boy’s having an extremely narrow trachea that does not grow. As with Castillo, the doctors used stem cells from the boy’s bone marrow and grew them on a cadaveric trachea (that had been stripped of its cells). However, unlike the transplant done with Castillo, with the boy the doctors added factors to prompt the stem cells to mature after they were transplanted into the boy (instead of maturing them entirely in a bioreactor), making the process much faster.

Beyond the work of Macchiarini and colleagues, other research groups have made breakthroughs in bioengineering different organs and tissues in the past few years. Researchers have been able to create and shape muscle segments using silicon-based synthetic scaffolds in the laboratory. Others have discussed the potential of using stem cells to rescue damaged heart muscles or create bioengineered intestines for transplantation. Mesenchymal stem cells (as used in the above airway transplants) hold great potential for healing wounds in general: These stem cells can turn into many different kinds of cells, be collected in large numbers, potentially migrate to areas they are needed in for healing, and be immunosuppressive. The combined use of stem cells with nanomaterials (which can mimic the surface of cells and tissues) holds much potential for future scaffold designs in regenerative medicine.

While successfully bioengineered and transplanted airways are breakthroughs, improvements will be needed to make such transplants feasible for a greater number of patients. Because Macchiarini’s groups used parts of organs from donors (the original cadaveric trachea segment), the transplants are still limited by available donors. It is hoped that research efforts will lead to fully-tissue-engineered organ transplants without the need of such donor grafts, helping address the current shortage of donor tissues and organs, to more effectively treat a large aging population.

The transition to the clinic of other stem cell-based regenerative therapies will also require extremely careful characterization of each individual procedure. There are still many obstacles to overcome before such therapies can become common practice, and those interested in receiving stem cell therapies should be aware of the possible risks involved; the Department of Health’s Gene Therapy Advisory Committee lists such potential hazards.

For more on using stem cells to create organs and tissues for transplants, see Teisha Rowland’s “All Things Stem Cell post on Bioengineering Organs and Tissues with Stem Cells: Recent Breakthroughs,” Paolo Macchiarini’s article on tissue-engineering tracheal transplantation, BBC coverage of “Windpipe transplant success in UK child,” The National Institute of Health’s Stem Cell FAQs, or, for a visual explanation of terms used, see All Things Stem Cell’s Visual Stem Cell Glossary.

Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at science@independent.com.