Every organ in our bodies performs a specialized role. So what happens when one of these organs fails or is damaged? Some animals can re-grow or replace lost tissue – newts can regenerate entire lost limbs – but unfortunately human organ regeneration is limited mainly to the liver. For decades, the only solution has been organ transplantation, but the demand for organs far exceeds the number of donors, which causes the waitlists for most transplants to be quite long. Also, transplants are not always successful, and it can be difficult to find a “donor match” which will be compatible with the patient’s body. However, as technology and researchers’ understanding of the human body have advanced, the field of tissue engineering is making some serious breakthroughs, and with this progress comes the promise of custom-made organs that could not only keep pace with demand, but also avoid rejection since they could be made with a patient’s own cells.
Tissue engineering combines the use of cells, organ scaffolds, and biosynthetic materials (materials designed to be compatible with the body) to improve or replace organs and tissues in the body. The cells on which researchers are most focused are stem cells [1,2]. Stem cells are important for their ability to “grow up” into any kind of cell in the body, which in turn makes them a promising tool for many medical treatments. Interestingly, organ scaffolding and biosynthetic materials that mimic natural scaffolding are proving to be equally important to researchers’ abilities to grow artificial tissues and organs.
The Importance of the Extracellular Matrix
Just as our body’s structure is dictated and held together by our skeleton, the size and shape of organs are dictated and held together by a mesh-like network called the extracellular matrix (ECM), also known as a scaffold. This scaffold is composed of large, rope-like proteins that assemble into a 3D network. Researchers once assumed this network existed primarily to hold cells together, but the ECM turns out to be essential for a range of other functions as well, and researchers are only beginning to fully understand its importance. Among its many roles, the ECM can generate signals to maintain the survival of cells growing within it, notify the body to send stem cells to promote new growth, facilitate cell movement, and even provide mechanical support to muscle cells when muscles contract. Recently, researchers have also begun demonstrating that the ECM of a particular organ may be sufficient to stimulate the growth of an entire new organ on its scaffolding [].
Researchers around the world are experimenting with scaffolding to take advantage of this phenomenon. At the Karolinska Institute in Sweden, scientists isolate organs such as hearts or lungs from rats and then strip the ECM of its cells, so that they are left with a heart- or lung-shaped mass []. Stem cells can then be added throughout the now-empty matrix; these cells subsequently grow into a heart or a lung or whichever organ the ECM originally supported (see figure, below). Scientists don’t know yet how the ECM prods these stem cells into becoming the right type of cells. The most tantalizing benefit to this therapy is that a patient’s own cells could be seeded onto the scaffold, thus bypassing the immune system rejection (where the patient’s own body attacks the transplant as a foreign threat) that has traditionally plagued transplant patients [].
Figure 1. Schematic for how the extracellular matrix (ECM) can be used to grow new organs. First, cells from the donor organ are washed off, leaving behind the ECM, which retains the general size and shape of the original organ. Then, the ECM is seeded with stem cells. Finally, the stem cells differentiate, or “grow up,” into adult cells for that organ – in this example, they would grow into heart cells.
Scaffolding: Biosynthetic versus Natural
It’s pretty exciting to take ECM from a rat heart and grow a new rat-sized heart, but how are these findings being translated to humans? Researchers are approaching this issue from two directions: designing synthetic scaffolds that mimic the shape and function of natural scaffolding, and using the ECM from animals that are similar to humans. At the Karolinska Institute, a cancer patient’s overgrown tumor necessitated the removal of his windpipe, so researchers built him an artificial windpipe. They designed a plastic copy of it, which they seeded with stem cells from his own bone marrow before stitching it into his body []. Bone marrow is the sponge-like interior of bones, and it contains stem cells that continuously produce new blood cells under normal conditions. This treatment has allowed him to survive cancer free for over a year. However, it is important to consider that this method of transplantation has limitations. While the plastic windpipe does not contain the types of foreign signals that a transplanted organ would have, and thus does not provoke the body to reject it, its presence still generates scar tissue that sometimes must be surgically removed. Also, a windpipe is one of the simplest organs in the body, as it is hollow and contains only a few layers of cells. More complex organs such as the heart or kidney would be significantly more complicated to model.
As they have begun grasping the limitations of biosynthetic materials and small animal models such as rats and mice, researchers are increasingly turning to animal models that are more physiologically similar to humans – those that have organs and cells with the same properties as our own – such as pigs, sheep, and even horses []. Using the ECM from a pig’s urinary bladder (which showed the best results in preliminary tests), doctors at the University of Pittsburgh Medical Center are helping patients regrow muscle tissue []. The sheet of scaffolding is implanted into patients in areas of muscle loss, where the body almost immediately begins breaking it down. Interestingly, breaking down the ECM releases signals that tell the body to send stem cells in order to replace the lost structure. These stem cells then grow into new muscle tissue in the damaged area.
Moving Forward
The ability to grow new tissue or organs is a huge step forward. However, a common element to both of the transplants mentioned above is simplicity: muscle tissue and windpipes, when compared to the rest of the body, are relatively straightforward to engineer. More complex organs contain multiple layers of distinct cell types, often organized in a specific arrangement that contributes to the function of the organ. But researchers are finding ways to tackle these issues, too. A team at the University of Toronto designed a machine that can place cells at specific locations within a synthetic matrix in order to mimic the growth of tissue during development, allowing them to grow large patches of living, functional tissue []; another researcher has demonstrated that the ECM can dictate a cell’s shape – which in turn dictates the function of that cell []. These and other advances in the field are important steps towards the ultimate goal of tissue engineering: understanding how organs and tissues grow so that we can manipulate them to develop into whatever each patient needs. Who knows? We may be only a couple of decades away from customized organ transplants being as routine as an appendectomy.
Ilana Kelsey is a PhD student in the Biological and Biomedical Sciences program at Harvard University.
References
[] Wade, Nicholas. “Cloning and Stem Cell Work Earns Nobel.” New York Times, 8 October 2012 <>.
[] Wai, Stephanie. “Giving Ordinary Cells the Superpowers of Stem Cells.” SITN Flash, 2007 <http://sitn.hms.harvard.edu/flash/2007/issue32/>.
[] Fountain, Henry. “A First: Organs Tailor-Made With Body’s Own Cells.” New York Times, 15 September 2012 <http://www.nytimes.com/2012/09/16/health/research/scientists-make-progress-in-tailor-made-organs.html?pagewanted=1>.
[] Tseng, Wen Allen. “Trials and Tribulations of a Transplant.” SITN Flash, 2012 <http://sitn.hms.harvard.edu/flash/2012/issue116/>.
[] Grimes, William. “Vets and Physicians Find Research Parallels.” New York Times, 10 September 2012 <>.
[] Fountain, Henry. “Human Muscle, Regrown on Animal Scaffolding.” New York Times, 16 September 2012 <http://www.nytimes.com/2012/09/17/health/research/human-muscle-regenerated-with-animal-help.html?pagewanted=1&ref=research>.
[] University of Toronto. “From Microns to Centimeters: Researchers Invent New Tissue Engineering Tool.” ScienceDaily, 31 July 2012 <http://www.sciencedaily.com/releases/2012/07/120731135001.htm>.
[] Massachusetts Institute of Technology. “Success of Engineered Tissue Depends on Where it’s Grown.” ScienceDaily, 14 August 2012 <http://www.sciencedaily.com/releases/2012/08/120814111001.htm>.