A pinboard by
Ettore Lignelli

Mad scientists are real!


Lizards regenerate their tails. Amphibians, whole body parts. What is wrong with us?

In 10 seconds? How come lower vertebrates like newts and salamanders can indefinitely regrow lost parts of their body? Scientists have been trying to understand this amazing phenomenon for around 250 years - and translate it to medicine. Here's what we know.

Cut, regrowth, rinse, repeat. Off with their limbs! And eyes. And spine. These wondrous prodigies always bounce back. There is much to learn and much more to understand before we can bridge the gap, as you can read here.

Isn't a lizard arm too different from a human arm in order to make this work? Not at all. Nerves, muscles, bones, joints - the structure's all there. That's why scientists are looking for species-specific factors that might be the "final ingredients" to unlock regeneration in humans. Take a look here as an example of how scientists are trying to solve this biochemical puzzle.

On a purely medical level, the possibilities are endless.

You could rebuild your body, one part at a time. Axolotl (Mexican salamanders) and newts can regrow retinas, heart, parts of the central nervous system. And we're getting closer every day to cracking their secrets. Browse pinboard

Cancer research could greatly benefit, too. There is a fine line between getting new cells to assemble into an organ and transforming them into a tumor. As reported here, newts walk this fine line pretty well. We need to understand exactly how.

Why transplant organs when you can grow them? Having a robust organ regeneration system could lead to crucial advancements in transplantation medicine; whenever an organ needs to be replaced, an identical one can be grown in the lab from a bunch of donor cells and used as a “spare part”.


Tissue regeneration in dentistry: can salamanders provide insight?

Abstract: The ability to regenerate damaged tissues would be of tremendous benefit for medicine and dentistry. Unfortunately, humans are unable to regenerate tissues such teeth, fingers or to repair injured spinal cord. With an aging population, health problems are more prominent and dentistry is no exception as loss of bone tissue in the orofacial sphere from periodontal disease is on the rise. Humans can repair oral soft tissues exceptionally well, however hard tissues, like bone and teeth, are devoid of the ability to repair well or at all. Fortunately, Mother Nature has solved nearly every problem that we would like to solve for our own benefit and tissue regeneration is no exception. By studying animals that can regenerate, like Axolotls (Mexican salamander), we hope to find ways to stimulate regeneration in humans. We will discuss the role of the transforming growth factor beta cytokines as they are central to wound healing in humans and regeneration in Axolotls. We will also compare wound healing in humans (skin and oral mucosa) to Axolotl skin wound healing and limb regeneration. Finally, we will address the problem of bone regeneration and present results in salamanders which indicate that in order to regenerate bone you need to recruit non-bone cells. Fundamental research, such as the work being done in animals that can regenerate, offers insight to help understand why some treatments are successful while others fail when it comes to specific tissues such as bones. This article is protected by copyright. All rights reserved.

Pub.: 05 Apr '17, Pinned: 14 Apr '17

Some principles of regeneration in mammalian systems.

Abstract: This article presents some general principles underlying regenerative phenomena in vertebrates, starting with the epimorphic regeneration of the amphibian limb and continuing with tissue and organ regeneration in mammals. Epimorphic regeneration following limb amputation involves wound healing, followed shortly by a phase of dedifferentiation that leads to the formation of a regeneration blastema. Up to the point of blastema formation, dedifferentiation is guided by unique regenerative pathways, but the overall developmental controls underlying limb formation from the blastema generally recapitulate those of embryonic limb development. Damaged mammalian tissues do not form a blastema. At the cellular level, differentiation follows a pattern close to that seen in the embryo, but at the level of the tissue and organ, regeneration is strongly influenced by conditions inherent in the local environment. In some mammalian systems, such as the liver, parenchymal cells contribute progeny to the regenerate. In others, e.g., skeletal muscle and bone, tissue-specific progenitor cells constitute the main source of regenerating cells. The substrate on which regeneration occurs plays a very important role in determining the course of regeneration. Epimorphic regeneration usually produces an exact replica of the structure that was lost, but in mammalian tissue regeneration the form of the regenerate is largely determined by the mechanical environment acting on the regenerating tissue, and it is normally an imperfect replica of the original. In organ hypertophy, such as that occurring after hepatic resection, the remaining liver mass enlarges, but there is no attempt to restore the original form.

Pub.: 26 Nov '05, Pinned: 14 Apr '17

Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine.

Abstract: While all animals have evolved strategies to respond to injury and disease, their ability to functionally recover from loss of or damage to organs or appendages varies widely damage to skeletal muscle, but, unlike amphibians and fish, they fail to regenerate heart, lens, retina, or appendages. The relatively young field of regenerative medicine strives to develop therapies aimed at improving regenerative processes in humans and is predicated on >40 years of success with bone marrow transplants. Further progress will be accelerated by implementing knowledge about the molecular mechanisms that regulate regenerative processes in model organisms that naturally possess the ability to regenerate organs and/or appendages. In this review we summarize the current knowledge about the signaling pathways that regulate regeneration of amphibian and fish appendages, fish heart, and mammalian liver and skeletal muscle. While the cellular mechanisms and the cell types involved in regeneration of these systems vary widely, it is evident that shared signals are involved in tissue regeneration. Signals provided by the immune system appear to act as triggers of many regenerative processes. Subsequently, pathways that are best known for their importance in regulating embryonic development, in particular fibroblast growth factor (FGF) and Wnt/beta-catenin signaling (as well as others), are required for progenitor cell formation or activation and for cell proliferation and specification leading to tissue regrowth. Experimental activation of these pathways or interference with signals that inhibit regenerative processes can augment or even trigger regeneration in certain contexts.

Pub.: 05 Jun '07, Pinned: 14 Apr '17

Current concepts in limb regeneration: a hand surgeon's perspective.

Abstract: Cognitive-behavioral practices such as meditation and yoga have long been viewed as methods of reaching states of peace and relaxation, but recent research has focused on the role of these practices in reducing endogenous mediators of stress and inflammation that would otherwise be harmful to our bodies. Further, these stress-related factors play major roles in inflammation, acting as barriers to wound healing and tissue regeneration. Fractures, denervation, tendon and ligament rupture, and cartilage degradation are morbidities associated with injury and often act as an impediment for healing. Studies of human fingertip regeneration exist; however, the underlying molecular and environmental changes have yet to be completely elucidated. Studying the regenerative capabilities of lower organisms and fetal wound healing has allowed scientists to understand the mechanisms behind regeneration, coming closer to a human application. Much research relies on the idea that the developing embryo shares a great deal in common with regenerating appendages of organisms such as the salamander. This review will cover historical perspectives of regeneration biology and current topics in limb regeneration, with particular interest given to the upper extremity, including the commonalities between human embryological development and amphibian regeneration, growth factors and pathways that show correlation with development and regeneration, recently discovered differences in fetal and adult wound healing, and current research and knowledge regarding human extremity tissue regeneration. With a greater understanding of the mechanisms and mediators involved in regeneration, the application of cognitive-behavioral practices may assist in seeing the future goals of regeneration come to fruition.

Pub.: 09 Sep '09, Pinned: 14 Apr '17

Applying amphibian limb regeneration to human wound healing: a review.

Abstract: In contrast to the limited regenerative ability found in human wound healing, which often results in unsatisfying and deficient scar formation, urodele amphibians, with the Mexican axolotl as a prime example, expose an extraordinary regenerative capacity. This regeneration leads to a perfect restoration of tissue architecture, function, and aesthetics with the axolotl being actually able to reclaim complete limbs. Evolutionary considerations suggest that regeneration might be a biologic principle which also underlies human wound healing. Experimental findings, such as comparative studies on transforming growth factor-β and fibroblast growth factor accentuate this assumption. Regeneration, as recent data indicate, might be a question of adaptive immunity. The loss of regenerative potency correlates with the decrease of regeneration in most species, whereas the Mexican axolotl lacks adaptive immunity throughout its life. The characterization of molecular pathways as a prerequisite for any control of regenerative processes sets an increasing indication toward the transfer into human beings. Some regenerative techniques, eg, recombinant transforming growth factor-β have already emerged. Molecular findings suggest that there is an intrinsic regenerative capacity in humans which might be initiated under appropriate circumstances. The Mexican axolotl is liable to diverse surgical and molecular approaches. Though well-known among developmental biologists, its exploitation for experimental Plastic Surgery still has to be established. We therefore intend to give an introduction to amphibian regeneration and the common evolutionary roots of regeneration and human wound healing, as we believe that Plastic Surgery takes a unique advantage of performing basic research on amphibian regeneration.

Pub.: 16 Oct '10, Pinned: 14 Apr '17

Muscle repair and regeneration: stem cells, scaffolds, and the contributions of skeletal muscle to amphibian limb regeneration.

Abstract: Skeletal muscle possesses a robust innate capability for repair of tissue damage. Natural repair of muscle damage is a stepwise process that requires the coordinated activity of a number of cell types, including infiltrating macrophages, resident myogenic and non-myogenic stem cells, and connective tissue fibroblasts. Despite the proficiency of this intrinsic repair capability, severe injuries that result in significant loss of muscle tissue overwhelm the innate repair process and require intervention if muscle function is to be restored. Recent advances in stem cell biology, regenerative medicine, and materials science have led to attempts at developing tissue engineering-based methods for repairing severe muscle defects. Muscle tissue also plays a role in the ability of tailed amphibians to regenerate amputated limbs through epimorphic regeneration. Muscle contributes adult stem cells to the amphibian regeneration blastema, but it can also contribute blastemal cells through the dedifferentiation of multinucleate myofibers into mononuclear precursors. This fascinating plasticity and its contributions to limb regeneration have prompted researchers to investigate the potential for mammalian muscle to undergo dedifferentiation. Several works have shown that mammalian myotubes can be fragmented into mononuclear cells and induced to re-enter the cell cycle, but mature myofibers are resistant to fragmentation. However, recent works suggest that there may be a path to inducing fragmentation of mature myofibers into proliferative multipotent cells with the potential for use in muscle tissue engineering and regenerative therapies.

Pub.: 12 Dec '12, Pinned: 14 Apr '17

Regeneration of soft tissues is promoted by MMP1 treatment after digit amputation in mice.

Abstract: The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.

Pub.: 26 Mar '13, Pinned: 14 Apr '17

Anterior Gradient 2 (AGR2) Induced Epidermal Growth Factor Receptor (EGFR) Signaling Is Essential for Murine Pancreatitis-Associated Tissue Regeneration.

Abstract: A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model. EGFR signaling and cell proliferation were examined in the context of the AGR2-/- null mouse or with the EGFR-specific tyrosine kinase inhibitor, AG1478. In addition, the Hippo signaling coactivator YAP1 was evaluated in the context of AGR2 expression during pancreatitis. Pancreatitis-induced AGR2 expression enabled EGFR translocation to the plasma membrane, the initiation of cell signaling, and cell proliferation. EGFR signaling and tissue regeneration were partially inhibited by the tyrosine kinase inhibitor AG1478, but absent in the AGR2-/- null mouse. AG1478-treated and AGR2-/- null mice with pancreatitis died whereas all wild-type controls recovered. YAP1 activation was also dependent on pancreatitis-induced AGR2 expression. AGR2-induced EGFR signaling was essential for tissue regeneration and recovery from pancreatitis. The results establish tissue regeneration as a major function of AGR2-induced EGFR signaling in adult higher vertebrates. Enhanced AGR2 expression and EGFR signaling are also universally present in human pancreatic cancer, which support a linkage between tissue injury, regeneration, and cancer pathogenesis.

Pub.: 21 Oct '16, Pinned: 13 Apr '17