Oxygen, Metabolism, and Regeneration: Lessons from Mice

The metabolic approach to regeneration can be viewed as being broad and deep. Part of our appreciation for the role of metabolism in regeneration has come from a rodent model of epimorphic regeneration, the MRL mouse. MRL mice exhibit a basal metabolic state of aerobic glycolysis, with increased levels of HIF-1α and NF-κB, increased levels of lactate, and reduced mitochondrial function. These processes have been implicated in inflammation and active chromatin remodeling that can lead cells to states of immature differentiation. The modulation of aerobic glycolysis and OX PHOS by drugs can lead to first a dedifferentiation state followed by a redifferentiation state returning new regenerated tissue back to normal architecture and normal function. We expect that the exploitation of metabolic plasticity will be a major medical theme in the future. The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians, and their ability to regenerate, to a mammalian context. We identified the ancient hypoxia-inducible factor (HIF)-1α pathway, operating through prolyl hydroxylase domain proteins (PHDs), as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans. The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians, and their ability to regenerate, to a mammalian context. We identified the ancient hypoxia-inducible factor (HIF)-1α pathway, operating through prolyl hydroxylase domain proteins (PHDs), as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans. FibroGen reports new research on development of HIF prolyl hydroxylase inhibitors related to endothelial progenitor cells, anti-inflammation, cytoprotection and erythropoiesis. http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=147534 mouse lines generated by intercrossing eight isogenic strains. Mice selected for their acute inflammatory reactivity (AIR) including cell infiltrates 24 h after subcutaneous injection of polyacrylamide particles. The AIRmax line has inflammatory infiltrates 25-fold greater than the AIRmin mice and genetic analysis has shown six inflammatory quantitative trait loci. AIRmax mice exhibit MRL-like ear hole closure, but the AIRmin mice do not. One of the loci, Slc11a1 in chromosome 1 or Nramp, is associated with ear hole closure. in development, aggregation of cells in the early embryo, capable of differentiation into specialized tissue and organs. It has a similar meaning in regenerating tissue where a mass of cells, undifferentiated and pluripotent, can develop at an injury site and grow into a normal organ or appendage. tissue-engineered biomaterials harboring different cell populations and can be implanted into the body to attempt growing new organs or tissues. component of the C1-complex pathway involved in complement activation as part of the innate immune response. C1q can bind to antibodies and is formed from 18 peptides formed into three subunits. collagen-containing C-type lectins; constitute a group of defense lectins known as soluble pattern recognition receptors involved in the innate immune response. part of the ear that resides outside of the head and is composed of skin and cartilage along with muscle and hair follicles. This is also called the auricle and focuses sound waves into the ear canal to be transmitted to the eardrum. type of regeneration defined in amphibians involving dedifferentiation of mature structures to form a mass of pluripotent cells known as the blastema just under a rapidly migrating population of epidermal cells. The regenerating blastema grows and forms a new limb or appendage with normal architecture and function. This occurs after an amputation injury. made by the liver, form a complex consisting of three related proteins plus a proteinase inhibitor, and circulate in the blood. Currently, it is not clear what the function of these proteins is since they are present in some species of hibernating mammals, but also in animals that do not hibernate. heterdimeric transcription factor HIF1 is comprised of two subunits, HIF-1α and HIF-1β. HIF-1α is a basic helix–loop–helix Per-Arnt-Sim (PAS) domain containing protein and is regulated through it interaction with prolyl-hydroxylating PHDs. As a transcription factor, HIF-1 is a master regulator of hypoxia-related genes including angiogenesis and vasculogenesis, energy metabolism, migration, and cell survival. HIF-1α⁄β functions as a transcription factor by binding to HREs in promoters with the sequence NCGTG where N=A or G. created from a pool of albino mice and then bred and selected for increased body size for >50 generations. Extensive genetic studies using this mouse strain have been carried out to examine bone length, obesity, and regeneration. originally generated to preserve the cn gene found in AKR mice. It was further bred to the C57BL/6 and C3H mouse strains and then to LG/J, with 75% of the genome being LG derived. It has been used to study systemic lupus erythematosis and Sjogren syndrome; found to have an unusual ability to regenerate a broad range of tissues. membrane-bound protein, also known as SLC11A1, is a divalent metal transporter within the endosomal and phagolysosomal membranes of iron-recycling macrophages and monocytes. It has been shown to be involved in ear hole regenerative responses in mice. branching off the glycolytic pathway at glucose-6-phosphate is the pentose phosphate pathway, which produces sugars that make up RNA and DNA but which neither produces nor uses up ATP but generates NADPH. 500-kDa ribonucleoprotein complex that incorporates one strand of a short (∼22 nucleotides) single-stranded miRNA or a double-stranded siRNA. This single strand acts as a RISC template to recognize cRNA. Argonaute 2, part of the complex, activates and cleaves the mRNA. This is a key process in gene silencing from drosophila to humans. multipotent cells found in mature skeletal muscle in mammals. After injury, this cell type is able to differentiate into mature skeletal muscle cells and allows muscle regeneration to occur. rodent mammal with three different species, Acomys kempi, Acomys percivali, and Acomys cahirinus; harbors unusual properties in skin shedding and rapid replacement of skin and, similar to the MRL mouse, closes ear holes and regenerates cartilage, adipose tissue, and hair follicles. This rodent is more related to gerbils than to mice. organisms that are able to regenerate lost limbs, appendages, and multiple organs such as planaria, starfish, hydra, sea cucumbers, amphibians, lizards (tails), deer (antlers), and MRL mice (ear holes, digit tissue, heart, etc.). Four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) that are highly expressed in embryonic stem cells and are involved in regulating the developmental signaling network required for embryonic stem cell pluripotency. Overexpression of these factors in both mouse and human somatic cells leads to a state of dedifferentiation and pluripotency and the generation of cell populations known as induced pluripotent stem cells used for regenerative replacement of tissue.