As humans age, hematopoietic stem cells—the immature precursor cells that give rise to all blood and immune cells—accumulate mutations. Some of the mutations allow these stem cells to self-renew and expand more effectively than their non-mutated counterparts. This relatively poorly understood condition, known as clonal hematopoiesis of indeterminate potential (CHIP), is detectable in more than 10% of people older than 65 and is linked to increased risks of various inflammation-related diseases.

"These mutations change the character of the progeny cells, making them more inflammatory," says Dr. George Hajishengallis of Penn Dental Medicine. "When a large fraction of your immune cells are derived from these mutant stem cells, it spells bad news for chronic inflammatory diseases."

Now, a team led by Hajishengallis, together with collaborators at the Dresden University of Technology and the University of North Carolina at Chapel Hill (UNC), have uncovered mechanistic insights into CHIP. They also found that an FDA-approved drug for preventing organ transplant rejection, rapamycin, has the potential to block these mutant stem cells and treat CHIP-driven inflammatory bone loss diseases, such as periodontitis and arthritis. Their research is published in the journal Cell.

"We found a compelling observational association between DNMT3A, a gene most commonly affected in CHIP, and the prevalence and severity of periodontitis in a cohort of 4,946 people aged 52 to 74," Hajishengallis says. "What's more, we corroborated these findings with our mouse model, demonstrating a strong causal relationship between DNMT3A mutations and increased susceptibility to inflammatory bone loss disorders. And most excitingly, we were able to show the efficacy of rapamycin in protecting mice from CHIP-exacerbated inflammatory bone loss, which paves the way for eventually treating such diseases in humans."

Considering potential therapeutic strategies Hajishengallis says, "Screening for CHIP among the elderly population may identify individuals with increased risk for inflammatory comorbidities."

These individuals may benefit from therapeutic interventions aiming to block the aberrant expansion of the CHIP-mutant hematopoietic stem cell clones and their adverse impact on chronic inflammatory comorbidities.

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