While U.S. soldiers fighting in Iraq and Afghanistan are surviving injuries that in previous conflicts likely would have been fatal, the number of wounded with major tissue loss has never before been so high.
Such injuries -- the partial or complete loss of digits or limbs and deforming facial injuries -- have profoundly affected the quality of life of the wounded as well as presented a new set of challenges for the medical community faced with treating them.
Recognizing the need for novel approaches that can restore, even partially, the structure and function of lost or damaged tissues, the Defense Advanced Research Projects Agency (DARPA) has awarded a $3.7 million grant to the University of Pittsburgh's McGowan Institute for Regenerative Medicine to oversee an ambitious, multi-center research program to better understand the intricate processes involved in wound healing and tissue restoration. A large part of the team's effort will involve examining the cellular and molecular systems that allow certain animals to completely regenerate lost tissue. The ultimate goal of the research is to identify ways for enhancing the capacity for wound healing and tissue restoration in humans.
Coordinating the effort is Stephen Badylak, D.V.M., M.D., Ph.D., research professor in the department of surgery at the University of Pittsburgh School of Medicine and Director of the Center for Pre-clinical Tissue Engineering at Pitt's McGowan Institute. In addition to the University of Pittsburgh, five other centers are involved. The investigators from these institutions offer diverse, yet complementary, research interests. They are:
- Susan Braunhut, Ph.D., professor of biological sciences at the University of Massachusetts at Lowell, a tumor cell and vascular cell biologist who studies the regenerative potential of extracellular matrix; and Kenneth Marx, Ph.D., professor of chemistry and a co-investigator of this team, who develops bioinformatics tools to analyze and model complex biological systems
- Lorraine Gudas, Ph.D., chairman of the pharmacology department and Revlon Pharmaceutical Professor of Pharmacology and Toxicology, Weill Medical College of Cornell University, New York City, an expert in retinoid pharmacology, stem cells and cell differentiation
- Ellen Heber-Katz, Ph.D., professor, molecular and cellular oncogenesis program, The Wistar Institute in Philadelphia, who previously identified a unique mouse model, the MRL mouse, with unusual regenerative properties and has been studying the genetics and the cellular, molecular and immune pathways involved in this response
- Shannon Odelberg, Ph.D., assistant professor, departments of internal medicine and neurobiology and anatomy, University of Utah, Salt Lake City, whose work focuses on the molecular basis for limb regeneration in newts
- Hans-Georg Simon, Ph.D., a developmental biologist and assistant professor of pediatrics, Children's Memorial Research Center and Northwestern University in Chicago, who studies the relationship between vertebrate limb development and limb regeneration
"We sincerely believe that the ability to promote tissue restoration in humans is not only possible; it will in fact be a reality some day. By working as a team and capitalizing on our collective expertise and experience, we're in a better position to succeed at unlocking the regenerative potential of mammals than would be possible working in the silos of our individual labs," said Dr. Badylak. The investigators believe their goal is attainable due to a convergence of recent discoveries made in their labs as well as at other institutions in the areas of stem cell research, extracellular matrix biochemistry and the regulation of gene expression.
To some extent, humans already have the capacity for regeneration. For instance, certain cells, such as liver cells and red blood cells, can self-renew; and during embryonic development, mammals and birds can regenerate such diverse tissues and structures as their skin and spinal cord. However, humans can't perform the same trick of regrowing a severed limb like salamanders or newts can. That is because in humans the cells that respond to the site of injury form scar tissue, whereas in salamanders the responding cells are genetically programmed to become the cell types of the lost structure, with full limb growth complete by two months.
When a salamander loses a limb, the wound sends out molecular signals that prompt surrounding tissue to begin production of new progenitor cells, also referred to as precursor cells. These progenitor cells continue to divide and form a large pool of cells at the wound site, called a blastema, that will later specialize and mature to help form the bone, muscle, cartilage, nerves and skin of the regenerated limb.
Although most mammals cannot restore tissue efficiently, a certain type of mouse, known as the MRL mouse, has enhanced regenerative capabilities. The MRL mouse can regenerate a portion of the ear as well as its heart tissue following injury.
The researchers aim to prove that mammals can form the required progenitor cells for regeneration just as a salamander does. By studying salamanders and MRL mice, the researchers hope to identify the specific types of cells, molecular signals, genes and cellular scaffolding required for regenerative cell growth. In essence, they seek as comprehensive an understanding as possible of the mechanisms and processes -- to obtain the blueprint for regenerative growth.
With such information in hand, the researchers will turn their attention to studies using another mouse model incapable of tissue restoration -- a model more representative of mammals, including humans. Specifically, they will attempt to orchestrate the formation of a blastema in response to an injury at the site where nature would normally direct the accumulation of scar tissue.
"If we succeed in being able to produce a regenerative response in a nonregenerative mammal, we will have overcome a major hurdle. Our next step would be to see, if following blastema formation, a functionally normal limb or digit develops. If we can achieve full restoration of function in a mouse or other mammal, it would seem feasible that we would be able to learn from this process and enhance the capacity for more efficient tissue restoration and wound healing in humans," commented Dr. Badylak.
The $3.7 million DARPA grant supports the project for one year. The agency could provide additional funding for up to three more years.