Oxygen, Metabolism, and Regeneration: Lessons from Mice

Abstract

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. In particular, the ancient hypoxia inducible factor (HIF-1α) pathway, operating through prolyl hydroxylase domain proteins (PHDs), was identified 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.

An injectable hydrogel‐formulated inhibitor of prolyl‐4‐hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis

“…23,24 An approach based on the transcription factor hypoxia-inducible factor (HIF)-1 was developed based on clues from unique regenerative traits of the Murphy Roths Large (MRL) mice. 24,25 HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits; whereas HIF-1β is constitutively expressed, HIF-1α is regulated by oxygen and accumulates in cells under hypoxic conditions. 26 The levels of HIF-1α are regulated by prolyl-4-hydroxylase (PHD) which, under normoxic conditions, hydroxylates proline residues on HIF-1α, thereby targeting it for degradation by the ubiquitin ligase-proteasome system.…”

“…27 Unlike most laboratory strains of mice, the MRL mouse exhibits an extraordinary capacity to regenerate tissues upon wounding, which has been attributed to their inherent ability to maintain high levels of HIF-1α in response to injury. 24,25 HIF-1α exerts pro-regenerative effects by transcriptional regulation of various genes involved in metabolism, angiogenesis, cell migration, and survival. 25,[28][29][30] Pharmacological inhibition of PHD activity, as by the use of 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), blocks the degradation of HIF-1α, and thus, increases its protein levels.…”

“…24,25 HIF-1α exerts pro-regenerative effects by transcriptional regulation of various genes involved in metabolism, angiogenesis, cell migration, and survival. 25,[28][29][30] Pharmacological inhibition of PHD activity, as by the use of 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), blocks the degradation of HIF-1α, and thus, increases its protein levels. 24,31 Importantly, systemic delivery of 1,4-DPCA via an injectable hydrogel carrier (1,4-DPCA/ hydrogel) in mice without spontaneous regenerative capacity, promoted tissue regeneration upon ear hole punch injury; this regenerative response was HIF-1α-dependent and reminiscent of that seen in MRL mice.…”

Damage-induced reactive oxygen species enable zebrafish tail regeneration by repositioning of Hedgehog expressing cells

“…7). Our model does not exclude the involvement of other signals such as TGFβ, EGF (Epidermal Growth Factor), hypoxia and non-canonical WNT signalling which are also likely to play roles in larval tail 2 9 8 regeneration 14,23,35,36 . Rather this model is intended to provide a framework for future 2 9 9 analysis of larval tail regeneration in fish.…”

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

“…A spontaneous mutation in the Fas lpr gene in this strain resulted in the substrain MRL/MpJ-Fas lpr , which develops signs of autoimmunity much earlier in life than the parent MRL/MpJ strain. [115][116][117][118] MRL/ MpJ-Fas lpr mice have a short lifespan (>50% mortality by 6 months old). They develop lymphoproliferative disease, immune complex glomerulonephritis, lupus-like skin disease, arthritis, and vasculitis.…”