Investigations of HIF-1a in MRL Regenerator Mice

The MRL mouse lineage is capable of unusual levels of tissue regeneration for a mammal, an entirely accidental discovery that emerged from an unrelated research program some years ago. Since this came to light, research groups have been chasing down the potential mechanism, and for much the same reason as scientists are interested in the details of salamander regeneration: the possibility of developing therapies to enhance human healing processes. Last I heard, the gene p21 was involved in MRL mouse regenerative capacity, but here researchers are proceeding down a different track, one that seems to have a fairly direct path to a first pass at a regenerative therapy for humans:

"We discovered that the HIF-1a pathway - an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development - can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration." The discovery is the latest development in a long investigation sparked by a chance observation in an unusual mouse strain. Almost 20 years ago, researchers noticed that the MRL mouse can spontaneously regenerate cartilage and other tissues after injury, making it a rare exception among mammals. Years of subsequent research involving the MRL mouse led the researchers to theorize that the HIF-1a pathway, which helps cells respond to low oxygen conditions, may also hold the key to the unique regenerative capability of MRL mice.

Under normal oxygen conditions, HIF-1a is degraded by prolyl hydroxylases (PHDs). Stabilization of HIF-1a levels can be accomplished through inhibition of PHDs. To test their theory, the researchers first experimentally down-regulated HIF-1a in MRL mice, which they found led to a loss of regenerative capability in the mice. Next, they selected a non-regenerating strain of mice to see what would happen when they experimentally up-regulated (stabilized) HIF-1a levels after an ear hole punch injury. The mice received three injections of a PHD inhibitor in a slow-release formulation at 5-day intervals. After 30 days, the researchers observed ear hole healing with closure and regrowth of cartilage and new hair follicles. In addition, the drug-treated mice showed a pattern of molecular changes indistinguishable from that observed in MRL mice during regeneration in response to injury, confirming HIF-1a as a central driver of healthy regeneration of lost or damaged tissue in mice.

"Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a. Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a." The researchers plan to move ahead to modify the drug delivery system to achieve an ideal formulation, which they will use to investigate regrowth potential in many types of tissues.

Link: http://www.eurekalert.org/pub_releases/2015-06/mlhl-sal060215.php

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