Acute organ failure can be fatal, even with the availability of intensive care and artificial organ replacements. Individuals who survive an episode of acute organ failure often develop chronic organ disease, which can result in significant long-term morbidity, mortality, and healthcare costs. However, the body does have an innate ability to try and repair damage, and emerging research supports the finding that there are two cell populations that will quickly respond and work together to restore an organ that is non-functioning or failing.
The surviving cells work to keep the organ functioning while other cells replace the damaged tissue. A new review article published in the journal Trends in Molecular Medicine now explores how this dual-response works and ultimately, save lives.
Even though vital organs such as the heart, liver, and kidney present very differently when injured, they do share a number of pathophysiological mechanisms. The researchers point out that two types of responses after acute organ failure appear to be shared in the liver, heart, and kidney. The parenchyma comprises the functional parts of an organ in humans, and the surviving differentiated parenchymal cells undergo cell hypertrophy via polyploidization, which is the state of a cell or organism having more than two paired sets of chromosomes. There is also a population of progenitors, which tend to be more immature, diploid (two sets of chromosomes), parenchymal cells that self-renew and differentiate to replace lost cells.
“When tissue is injured, cells divide to replace it, but the process of cell division in specialized cells would prevent the cell from performing its normal duties,” said Paola Romagnani, MD, a professor of nephrology at the University Meyer Children’s Hospital of Florence, Italy, in a statement. “In situations where an organ is failing, which means the organ already isn’t functioning properly, your body can’t afford to have many cells stop working.”
She noted that up until recently, “It was believed that function recovery after injury was a consequence of regeneration involving all specialized cells simply ignoring that such cell divisions would imply a further potentially life-threatening decline of residual organ function.”
Therefore, they point out in their paper that essential organs such as the heart, liver, and kidney avoid widespread cell proliferation that would be largely counterproductive because it implies a transient loss of the specialized cellular functions. Instead, these organs require polyploidization or the ability of the stem-like cells to rapidly divide and replace damaged tissues.
Cooperation between the two cell types is important because of their distinct functions. The specialized cell will replicate its DNA, but will not divide, a process known as endoreplication. In this manner, the cell is still able to function and help compensate for the cells that were destroyed during the injury. Simultaneously or right after cells endoreplicate, the stem-like cells rapidly divide to replace the destroyed tissue.
Dr. Romagnani and colleagues found that some organs rely more heavily on one technique than the other. As an example, the heart has smaller densities of stem-like cells than the liver, and so the heart responds to organ failure largely with endoreplication of specialized cells rather than cell regeneration. In contract, cell regeneration occurs more readily in the liver.
The authors note that rapid compensation of function loss assures survival of the organ, and both mechanisms act synergistically for organ function recovery. A better understanding of these mechanisms has implications for developing therapeutics that may encourage one response over the other, given the specific situation.
“Endoreplication is a way to quickly increase cell size and function undergoing hypertrophy, which is great in the short term because it can save a life,” Romagnani said. “But in the long run, having a high proportion of cells in this state can result in chronic organ dysfunction due to the breaking-down of tissues.”
Having too much cell division in stem-like cells can also lead to long term problems. While tissue strength is improved, this risk of developing cancer in the affected organ is also greater.
“When you have a high number of cells that are efficient at dividing, you have a higher risk of cancer,” Romagnani explained. “These significant tradeoffs are likely why both methods exist and why it’s so important for them to be balanced.”