In most situations, building an implantable tissue from a patient’s own cells would be ideal because they are compatible with that person’s immune system. Realistically, such implants might also face fewer regulatory hurdles because the material is derived from the patient’s own body. The ability of normal cells to multiply in culture is limited, however, making it difficult to generate sufficient tissue for an implant. Socalled adult stem cells from the patient’s body or from a donor are somewhat more prolific, and they can be isolated from many sources, including blood, bone, muscle, blood vessels, skin, hair follicles, intestine, brain and liver.
Adult stem cells—which occur in adult tissues and are able to give rise to a variety of cell types characteristic of their native tissue—are difficult to identify, however, because they do not look very different from regular cells. Scientists therefore must look for distinctive surface proteins that serve as molecular markers to flag stem cells. The identification of additional markers would make it considerably easier to work with adult stem cells in tissue-engineering applications. Fortunately, over the past few years a number of major advances have been made, including development of novel methods of isolating the cells and inducing them to proliferate and to differentiate into various tissue types in culture.
Notably, Christopher Chen and Dennis Discher, both at the University of Pennsylvania, have demonstrated that mesenchymal stem cells, which are typically derived from muscle, bone or fat, will respond to mechanical cues from their surroundings. They have been shown to endifferentiate into the tissue that most closely resembles the stiffness of the substrate material on which they are growing. Other researchers have also shown that chemical signals from the substrate and surrounding environment are important for directing the differentiation of adult stem cells into one tissue type or another. Scientists disagree, though, about whether adult stem cells are able to give rise to cells outside their own tissue family—for instance, whether a mesenchymal stem cell could generate liver cells.
In contrast to adult stem cells, embryonic stem (ES) cells are easy to expand in culture and can differentiate into all the cell types of the human body. Langer, along with Shulamit Levenberg of the Technion-Israel Institute of Technology in Haifa and her colleagues, has demonstrated that ES cells can even be made to differentiate into a desired tissue type right on tissue-engineering scaffolds. This capability suggests the potential to make 3-D tissues on scaffolds directly from differentiating ES cells. These cells do present various challenges, however.
Directing the uniform differentiation of ES cells into the desired cell types is still quite difficult. In attempts to mimic the complex natural microenvironment of ES cells and to optimize their differentiation, investigators are testing many conditions simultaneously to find the right combination of cues from different materials and matrix chemicals. They are also screening various small molecules as well as signaling proteins to identify factors that control “stemness”—the cells’ ability to give rise to differentiated progeny while remaining undifferentiated themselves, ready to produce more new cells as needed.
Those insights could also be applied to producing cells with the capabilities of embryonic cells but fewer of the drawbacks. Beyond the difficulties just outlined, scientists are still unable to predict the behavior of transplanted stem cells in patients. Undifferentiated ES cells can form tumors, for instance, creating a risk of cancer if the cells are not all successfully differentiated before transplantation. In addition, researchers have been making efforts to address the ethical issues associated with deriving ES cells from human embryos by exploring approaches to producing ES-like cells from nonembryonic sources.
In the past couple of years remarkable progress has been made in producing ES-like cells from regular adult body tissue, such as skin cells. These altered cells, known as induced pluripotent stem (iPS) cells, are emerging as an exciting alternative to ES cells as a renewable resource for tissue engineering. In 2007 Shiro Yamanaka, then at Kyoto University, and James A. Thomson of the University of Wisconsin–Madison first showed that cells of adult tissue can be transformed to a primitive iPS state by reactivating a number of genetic pathways that are believed to underlie stemness. Reintroducing as few as four master regulatory genes into adult skin cells, for instance, caused the cells to revert to a primitive embryonic cell type. The early experiments used a virus to insert those genes into the cells, a technique that would be too dangerous to use in tissues destined for patients. More recent research has shown that a safer nonviral technique can be adapted to activate the same repertoire of stemness genes and even that activation of just a single regulatory gene may be sufficient. The rapid progress in this area has tissue engineers hopeful that soon a patient’s own cells, endowed with ES cell capabilities, could become the ideal material for building tissue constructs. And even as we experiment with these different cell types, tissue engineers are also refining our building methods.
Source of Information : Scientific American(2009-05)