Stem Cell Regenerative Medicine is the controlled differentiation of stem cells into the functionally defined cells required to mend or replace sick or damaged tissue or organs. Our bodies do this naturally, generating rather than regenerating a complete body from a single cell, growing and maintaining the body during our early years, maintaining it during adulthood, and then somehow allowing the process to deteriorate as the body ages and finally dies.
Shedding some new light on the process of aging and death, It turns out that the loss of two proteins, the tumor-suppressor protein p53 and the DNA-maintenance protein ATR, results in tissues deteriorating rapidly generally resulting in death.
Essentially, argued senior author Eric Brown, PhD, Assistant Professor of Cancer Biology at the University of Pennsylvania School of Medicine, the findings highlight the fact that day-to-day maintenance required to keep proliferative tissues like skin and intestines functional is about more than just regeneration, the stem cell-based process that forms the basis of tissue renewal. It's also about housekeeping, the clearing away of damaged cells.
"An analogy to our findings is what happens to trees during the changing seasons," said Brown. "In springtime, leaves are new and undamaged. But as the summer wears on, the effects of various influences - insects, drought, and disease - cause them to lose the pristine qualities they once had. However, the subsequent fall of these leaves presents a unique opportunity for regeneration later on, a chance to rejuvenate from anew without pre-existing obstacles. Similarly, by suppressing the accumulation of damaged cells in tissues, p53 permits more efficient tissue renewal when ATR is deleted."
Cells without ATR that remain uncleared may block tissue regeneration either by effectively refusing to relinquish space to undamaged cells, or by secreting signals that halt regeneration until they have been removed.
"These results came as something of a surprise," said Brown. Previous studies pairing DNA-repair mutations with p53 mutations always led to a partial rescue of the DNA repair mutation "We think this happens because p53 loss helps cells with just a little DNA damage to continue to contribute to the tissue." At a minimum, the team expected nothing to happen.
"But we got the opposite result," said Brown. "Absence of p53 did not rescue the tissue degeneration caused by ATR loss, it made it much worse. This result suggested that allowing mutant cells without ATR to persist is more harmful to tissues than eliminating them in the first place." Brown speculates that could be because the ATR mutation produces much more damage than most other DNA-repair defects.
According to Brown, their findings and those of other laboratories also reinforce the potential of a new therapeutic for cancer. That's because, among their other discoveries, the team noticed that cells missing both ATR and p53 have more DNA damage than those missing either gene alone. As a large fraction of human cancers have p53 mutations, he said, "p53-deficient tumors might be especially susceptible to ATR inhibition." Indeed, clinical trials already are underway involving an ATR partner protein called Chk1. "Our study provides supportive evidence for the potential use of ATR/Chk1 inhibitors in cancer therapy," says Brown
Adapted from the University of Pennsylvania School of Medicin announcement.
Comments