Genetic perturbation of cellular homeostasis regulates integrated stress response signaling to control <i>Drosophila</i> hematopoiesis

Aging results in a decline in cellular and molecular functions. One of the hallmarks of aging is stem cell exhaustion, which impacts self-renewal and differentiation. We employ the Drosophila larval lymph gland (LG) to investigate the impact of genetic perturbation of cellular homeostasis on hematopoiesis. The LG consists of a posterior signaling center (PSC) - a stem cell niche that maintains medullary zone (MZ) prohemocytes, whereas the cortical zone (CZ) consists of differentiated hemocytes. We employed over-activation of Toll or Imd pathway to disrupt cellular homeostasis, whereas we over-expressed Foxo or Atg8 to balance it. Genetic perturbation of cellular homeostasis displays hallmarks of aging. Induction of Toll or Imd pathway locally and systemically leads to a decreased niche size and increased differentiation, whereas Foxo or Atg8 over-expression shows an opposite trend. We showed that the integrated stress response (ISR) pathway is induced upon Toll or Imd over-activation and LGs with ISR perturbation show increased hemocyte differentiation. Genetic epistasis shows that ectopic over-expression of ISR components upon Imd activation can rescue hematopoietic defects. Overall, our study explores how genetic perturbation of cellular homeostasis can impact hematopoiesis. Our research has implications in understanding how abrogation of cellular homeostatic mechanisms may lead to onset of malignancies.