Taking our first breaths marks the beginning of a new life, yet this may be the very act that limits our ability to grow and heal as adults. Studies in mice have pinned down a newborn鈥檚 exhalation of carbon dioxide, immediately after birth, as the starting gun that switches off their cells鈥� intrinsic ability to regenerate.
鈥淲e were very surprised and excited by the CO2 effect,鈥� says at Harvard Medical School, who led the research.
But when grown mice inhaled the gas, the regenerative pathways turned back on, a discovery He hopes could lead to targeted medical treatments. The results are聽鈥渧ery tantalising鈥�, says at McGill University in Canada. 鈥淚f correct, this is a groundbreaking discovery.鈥�
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Many species of fish, amphibians and reptiles can regenerate tissues, limbs and organs such as hearts, following injury. Mammals also have some regenerative capacity before and shortly after birth, but lose this later in life. A protein master switch called mTOR is one reason they do so. It plays a central role in regulating cell growth in tissues such as brain, heart and muscles, and its activity declines inside cells within minutes of birth. But the reasons for the drop were poorly understood, says at the University of Illinois, who wasn鈥檛 involved with the latest research.
Zhigang He and his colleagues wondered if the shutdown could be related to the dramatic event of birth itself. To find out, they tracked mTOR activity in neurons in the retinas of mice delivered by caesarean section. As long as the newborns remained inside an intact amniotic sac, mTOR stayed high. But as soon as they were removed from the sac and the pups began to breathe air, mTOR activity dropped, even if the researchers kept the umbilical cord intact so that the nutrient supply from the mother was unchanged. This suggested the shutdown trigger was the transition from receiving oxygen through the blood of the umbilical cord to independently breathing air.
The researchers also confirmed that temperature wasn鈥檛 a factor in the shutdown through separate tests in which newborn pups were kept at the same temperature 鈥� 37掳C 鈥� as they had experienced in the uterus.
Next, the team delivered pups in controlled gas environments, and found that mTOR activity still shut down even if they lowered oxygen levels in the air. But increasing CO2 levels to 10 per cent prevented the loss of mTOR activity.
Further experiments showed that exhaling CO2 triggers the mTOR shutdown by causing a rise in pH inside cells as levels of the gas fall.
When adult mice inhaled air containing 10 per cent CO2, mTOR activity restarted across a range of tissues including brain, heart and muscle, and their neurons鈥� ability to regenerate after injury was restored. The work shows that the drop in CO2 when breathing starts is 鈥渢he underlying mechanism driving regenerative failure, not only in neurons but potentially across multiple organs鈥�, says Tahmasebi, 鈥渁nd importantly it is reversible鈥�.
CO2 exhalation might not be the only factor governing the ability of cells to regrow, says He. 鈥淥ther physiological changes associated with birth may also influence regenerative capacity.鈥� But he hopes the discovery could lead to the development of simple, non-invasive therapies, perhaps based on inhaling CO2, for conditions such as spinal cord injury or traumatic brain injury.
Inhibiting mTOR, with drugs such as rapamycin, has previously been shown to have anti-ageing effects in many species including humans, whereas activating it rescues embryonic-like regenerative potential, at least in mice, but can cause cells to grow out of control, says Tahmasebi. The risk of cancer has deterred industry investment in drugs that activate mTOR, he says, but perhaps the role of CO2 could lead to ways to activate the cascade more safely, in a 鈥渢emporary and tissue-specific鈥� way.
Further research is still needed, however, to establish appropriate and safe CO2 levels and exposure times, as well as potential side effects. 鈥淲e would not recommend attempting this without medical supervision,鈥� says He.
The connection between air breathing and regenerative potential also has intriguing evolutionary implications. Vertebrates that acquire oxygen via gills and lose CO2 via their skin 鈥� some fish species, as well as amphibians during aquatic larval stages 鈥� tend to have high capacity for regeneration, whereas mammals and birds, dependent on air and lungs, are generally much more limited. Breathing could therefore be an underappreciated evolutionary factor shaping regenerative abilities across many forms of life, the researchers say.
bioRxiv
