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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Adv Drug Deliv Rev. 2018 Mar 7;129:254–261. doi: 10.1016/j.addr.2018.02.006

Fig. 1.

Fig. 1

A) Eukaryotic single cell organisms with mitochondria (ie yeast, far left panel) prospered using plant-derived glucose and atmospheric oxygen to efficiently generate ATP. This allowed further evolution to metazoans or multicellular life (ie hydra and sponges, middle panels). High oxygen levels present problems for cells and therefore must be regulated. The toxic properties of oxygen are regulated by PHDs and HIFα’s where with high O2 levels, PHDs are active and hydroxylate HIFα prolines leading to HIFα degradation with a concomitant oxidative phosphorylation metabolic state, increased differentiation, and reduced proliferation (87). With low levels of O2, leading to hypoxic conditions, PHDs are inactive, HIFα prolines are not hydroxylated and HIFα is not degraded and shows increased protein levels (stable HIFα). HIFα now can move into the nucleus, and together with HIF1β, acts as a transcription factor activating genes specific for the glycolytic metabolic state, cell de-differentiation, amino acid, DNA, and lipid synthesis and enhanced cell proliferation. The regenerative MRL mouse (far right panel) during regeneration displays a biphasic response. Phase I (da 0–14 post injury) shows characteristics of a low level O2 state with high levels of HIFα, increased de-differentiation and proliferation. This is followed by Phase II (da 15–30 post injury) in which a higher O2-type response with decreased HIFα, re-differentiation, and reduced proliferation are seen. Both Phases appear to be necessary to achieve a full regenerative healing response, first breaking down tissue and then rebuilding it (62, 86). B) To recreate regeneration in non-regenerating mice, a delivery system using crystallized PHD inhibitor (1,4-DPCA) encapsulated in a PEG hydrogel (Gd) slowly releases drug C) which is given at multiple timepoints (da 0, 5, and 10) to induce a Phase I response. As drug levels decline by day 15, Phase II ensues, D) resulting in a 30 day regenerative complete ear hole closure response identical to that observed in the spontaneously regenerating MRL mouse. Gel without drug shows little healing (G0). (from Zhang (62) Fig 4).