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March 24, 2008

Enabling regeneration in humans: Developing a roadmap

What is required to enable effective limb regeneration in humans in detail ? by Ken Muneoka [Professor Department of Cell and Molecular Biology at Tulane University]
, Manjong Han [Professor Department of Cell and Molecular Biology at Tulane University] and David M. Gardiner Researcher, Developmental & Cell Biology
School of Biological Sciences at U of California at Irvine.

Researchers now understand in detail the steps that occur when a salamander regenerates a limb and they understand the differences for human scarring and human fetal regeneration or limb growth. The early responses of tissues at an amputation site are not that different in salamanders and in humans, but eventually human tissues form a scar, whereas the salamander’s reactivate an embryonic development program to build a new limb. Learning to control the human wound environment to trigger salamanderlike healing could make it possible to regenerate large body parts. A few years to get really good at making mice regenerate and then another ten years to make it happen in humans and get the process approved by regulatory authorities.

The one human tissue type within a limb that lacks regenerative ability is the dermis, which is composed of a heterogeneous population of cells, many of which are fibroblasts—the same cells that play such a pivotal role in the salamander regeneration response. After an injury in humans and other mammals, these cells undergo a process called fibrosis that “heals” wounds by depositing an unorganized network of extracellular matrix material, which ultimately forms scar tissue. The most striking difference between regeneration in the salamander and regenerative failure in mammals is that mammalian fibroblasts form scars and salamander fibroblasts do not. That fibrotic response in mammals not only hampers regeneration but can be a very serious medical problem unto itself, one that permanently and progressively harms the functioning of many organs, such as the liver and heart, in the aftermath of injury or disease.

Studies of deep wounds have shown that at least two populations of fibroblasts invade an injury during healing. Some of these cells are fibroblasts that reside in the dermis, and the others are derived from circulating fibroblastlike stem cells. Both types are attracted to the wound by signals from immune cells that have also rushed to the scene. Once in the wound, the fibroblasts migrate and proliferate, eventually producing and modifying the extracellular matrix of the area. This early process is not that dissimilar to the regeneration response in a salamander wound, but the mammalian fibroblasts produce an excessive amount of matrix that becomes abnormally cross-linked as the scar tissue matures. In contrast, salamander fibroblasts stop producing matrix once the normal architecture has been restored.



Our research group has already described a natural blastema in a mouse amputation injury, and our goal within the next year is to induce a blastema where it would not normally occur. Like the accessory-limb experiments in salamanders, this achievement would establish the minimal requirements for blastema formation. We hope that this line of investigation will also reveal whether, as we suspect, the blastema itself provides critical signaling that prevents fibrosis in the wound site.

If we succeed in generating a blastema in a mammal, the next big hurdle for us would be coaxing the site of a digit amputation to regenerate the entire digit. The complexity of that task is many times greater than regenerating a simple digit tip because a whole digit includes joints, which are among the most complicated skeletal structures formed in the body during embryonic development. Developmental biologists are still trying to understand how joints are made naturally, so building a regenerated mouse digit, joints and all, would be a major milestone in the regeneration field. We hope to reach it in the next few years, and after that, the prospect of regenerating an entire mouse paw, and then an arm, will not seem so remote.


Understanding how limbs are formed

Limbs are formed by a series of interactions that occur between a specialized group of ectodermal cells at the tip of the limb bud that forms a structure called the apical ectodermal ridge (AER), and the mesenchymal cells that underlie the AER. The apical ectoderm produces factors that are necessary for distal outgrowth by the mesenchyme. Mesenchymal cells interact with one another and with the AER to establish spatially distinct patterns of gene expression followed by the differentiation of specific structures. The primary focus of my research is to understand how cells become distinct from one another. In the 1980’s Ken Muneoka cell lineage work on developing and regenerating amphibian limbs demonstrated similarities between development and regeneration, and also established the over-contribution of fibroblasts in the regeneration response. To begin to address regeneration in higher vertebrates, Ken Muneoka pioneered in utero surgical techniques that make it possible to carry out regeneration studies on the developing mammalian limb. In the early 1990’s Ken Muneoka participated with Susan Bryant’s lab in a study that demonstrated retinoic acid acted to induce a mesenchymal signaling center in the limb bud called the Zone of Polarizing Activity (ZPA). This finding has now been demonstrated with loss of function studies and with more sophisticated molecular probes with the same conclusion.


FURTHER READING
Digit regeneration in fetal Mice is regulated by Msx1 and BMP4 [2003]

Limb regeneration in higher vertebrates : Developing a roadmap [2005]

Regenerating Life [2005]

The University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center have established the McGowan Institute for Regenerative Medicine

national center of expertise in regenerative medicine focused on developing and delivering therapies that reestablish tissue and organ function impaired by disease, trauma or congenital abnormalities


Tissue Engineering and Biomaterials

Cellular therapies

Medical devices and artifial organs

Tengion, a clinical stage biotechnology company, has pioneered the Autologous Organ Regeneration Platform™ that catalyzes the body's innate ability to regenerate.

Tengion Launches Third Phase 2 Clinical Trial of Regenerated Human Bladder


Tengion is also working on a neo-kidney (not in clinical trial yet) and Tengion Neo-Vessel™ Neo-vessels are being developed with the goal of using a patient's own cells to build blood vessels for patients that need vascular access for dialysis and for patients who are receiving peripheral by-pass surgery or coronary artery bypass surgery.

CBS news coverage of regenerative medicine progress.

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