Activated Lin28a enhances tissue repair (Regrow Hair, Cartilage, Bone, Soft Tissues)

[Berryboy]

http://www.cell.com/retrieve/pii/S0092867413012786

Interesting paper looking at the reactivation of Lin28a, a gene expressed in embryonic stem cells. They genetically engineer mice to express the Lin28a gene in response to the drug, doxy-cycline (DOX). These modified mice have thicker hair and thicker skin. The hair also seems to have extended periods of anagen and shortened telogen.

Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics.

Interestingly, Lin28a seems to increase Oxidative Phosphorylation, which inself seems to lead to regeneration.This effect can be produced directly in wildtype mice by topical application of 2-deoxy-D-glucose or 3-Bromopyruvate (both glycoysis inhibitors and proposed anticancer agents).

Surprisingly, daily topical application of glycolysis inhibitors(3BP or 2-deoxy-D-glucose [2DG]) induced a substantial enhancement in WT tissue repair, comparable to the Lin28a-mediated enhancement (Figure 7D). 3BP also enhanced migration in WT MEFs (Figure 6D). One possible result of glycolysis inhibition is a compensatory increase in OxPhos activity, a phenomenon observed in cancer cells (Wu et al., 2007). To test whether a compensatory increase in OxPhos explains why glycolysis inhibition in WT ears enhances tissue repair similarly to Lin28a overexpression (Figure 7D), we performed metabolomic profiling on WT ears 1 and 7 days after daily 3BP treatment. At 1 day after topical treatment, we found that 3BP drastically reduced glycolytic intermediates and decreased the NADH/NAD, ATP/AMP, ATP/ADP, and GTP/GMP bioenergetic ratios, as expected with glycolysis inhibition (Figure 7E). After 7 days of daily 3BP treatment, however, the levels of glycolytic intermediates and the NADH/NAD ratio returned to normal, and there was a significant increase in the ATP/AMP and ATP/ADP ratios, indicating a compensatory increase in OxPhos activity in vivo (Figure 7E). In WT MEFs, 3BP also led to an increase in 13C-glucose flux through the Krebs cycle
(Figure 7F) and an increase in the maximal O2 consumption rate (Figure 7G), further confirming that chronic glycolysis inhibition by 3BP induces a compensatory increase in OxPhos to enhance tissue repair.

So can we get hold of either 3BP or 2-deoxy-D-glucose and try it topically, maybe also adding to the dermarolling regime too.

Berryboy