Isak W. Tengesdal, PhD | Department of Pathology, Stanford Medicine
Competition Sponsor: National Academy of Medicine
Awardee Year: 2024
Age-related chronic inflammatory diseases represent a major incoming burden as the proportion of the world’s population over 60 years is expected to jump to 22% by 2050 according to the World Health Organization. Inflammation is caused by production of small proteins, termed cytokines. As we age, our tissues and organs are constantly seeded by a pool of hematopoietic stem cells (HSCs) that become mature immune cells in the new tissue. This is thought to maintain tissue homeostasis, however, in age-related diseases it appears that increased tissue inflammation causes tissue damage resulting in disease. Therefore, understanding how increased cytokine production occurs remains pivotal to preventing and treating age-related diseases. Recently, it has been revealed that certain mutations accumulate in our HSCs which give the HSCs harboring these mutations preferential expansion compared to non-mutated HSCs as well as a hyperinflammatory phenotype. This process is termed clonal hematopoiesis of indeterminate potential (CHIP) and can be detected using next-generation sequencing in blood. CHIP is very common, affecting greater than 10-30% of those aged 70 years and older and is associated with increased mortality and with age-related, chronic inflammatory diseases such as atherosclerosis, liver disease, gout, osteoporosis and metabolic disorders. This is thought to occur due to excessive inflammation from cells carrying CHIP mutations. We present herein a humanized CHIP model to study the dynamics of this system and assess; (1) how different inflammatory cytokines affect hematopoiesis in CHIP; (2) a method for characterizing tissue cellularity in the setting of CHIP.