Research Summary: Our research explores how hematopoietic progenitors respond to various stresses by activating protective mechanisms, revealing how stem cells adapt and preserve tissue health and resilience, especially during aging.
Co-First authors: Kishalay Ghosh & Rohit Iyer
Kishalay – Through his perseverance, independent thinking, and integrity, Kishalay brings vision and analytical rigor to every pursuit. He began his neuroscience PhD at the Paris Brain Institute last year—his long-standing goal.
LinkedIn: https://www.linkedin.com/in/kishalay-ghosh-4137a5147/
Twitter: https://x.com/Kishalay_ish
Instagram: ekta_kalboishakhir_golpo
Rohit – Rohit is a positive, motivated, and persistent researcher who embraces life’s lessons, striving to always give his best in every endeavour. He is currently actively applying for PhD positions in Europe in the fields of parasitology, genetics, and stem cell biology.
LinkedIn: www.linkedin.com/in/rohit-krishnan-iyer-934461189
Instagram: rohit_krishnan005
Lab: Dr. Rohan Khadilkar (Stem Cell & Tissue Homeostasis Lab), Cancer Research Institute, ACTREC
Lab website: https://scthlab.wixstudio.com/scthlab/blank
Genetic perturbation of cellular homeostasis regulates Integrated Stress Response signaling to control Drosophila hematopoiesis
What was the core problem you aimed to solve with this research?
This study aims to uncover the effects of modulating the molecular circuitry of cellular homeostasis on hematopoiesis in the Drosophila lymph gland and understand its cell-intrinsic and extrinsic regulation and how its perturbation in both genetic and chemical manners can impact hematopoiesis. Now, in the lymph gland, there is a homeostatic balance maintained between the progenitors and terminally differentiated hemocytes. When the stress of inflammation was introduced in different regions of the lymph gland, this homeostatic balance was disrupted and skewed more towards differentiation. We aimed to investigate how the progenitors and other lymph gland subsets respond to chronic stresses, and whether homeostasis is permanently disrupted or restored over time.
How did you go about solving this problem?
We developed Drosophila models with constitutive activation of the immune pathways, like Imd and Toll pathways, in the lymph gland, mimicking a chronically inflamed state. This led to premature differentiation of blood progenitors into mature hemocytes, reflecting disrupted hematopoiesis under immune stress. We wanted to find out if any established protective mechanisms like the UPR (Unfolded protein response), DDR (DNA damage repair), or ISR (Integrated stress response) signalling pathways are active and upregulated to tackle the chronic stress. We then went ahead and focused on the Integrated Stress Response (ISR) as a potential regulator of cellular homeostasis in this context, due to its ability to provide a cumulative and integrated response of adaptation and survival against all forms of stress.
We then activated the components of ISR signalling like Gcn2 in the background of chronic inflammation using both genetic (e.g., Gcn2 over-expression) and pharmacological-based interventions, and observed a clear rescue of the aberrant differentiation phenotype and restoration of homeostasis. This suggests that chronic inflammation exerts its effect not just through immune signaling but also by overwhelming the cell’s homeostatic capacity—something the ISR can buffer.
To dissect the source of stress further, we used tissue-specific drivers and genetic mosaics to separate cell-intrinsic effects from micro-environmental influences. Imaging, lineage markers, and stress reporters helped validate our observations.
Altogether, this project gives good insights about how perturbation of cellular homeostasis in the lymph gland causes defects in hematopoiesis, and that these defects can be countered by stress-responsive signalling like ISR that helps the cells to adapt and recoup, and restore the hematopoietic balance.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Our body has hematopoietic stem cells in the bone marrow that divide and produce new blood cells, replacing different types of old, dysfunctional, differentiated blood cells. There is a homeostatic balance existing between the stem cells and the terminally differentiated cells, which is maintained under normal conditions, and any dysregulation in this homeostasis can result either in overproduction of new cells and subsequent formation of cancer, or inadequate division of them results in tissue degeneration. In our lab, we mainly work on the lymph gland, a hematopoietic organ (which is similar to bone marrow in humans) in the fruit fly (Drosophila) that houses the hematopoietic stem cell-like progenitors. We induce the stress of inflammation and oxidative stress in different cell types of the lymph gland and look at whether the homeostatic balance is still maintained or skewed towards one side. In our study, we observed that the homeostatic balance under the above-mentioned stresses gets disrupted and leans more towards differentiation. In such a case, stress-responsive pathways like the ISR get activated and help them to adapt and counter stress in order to restore the homeostatic balance and survive.
What are the potential implications of your findings for the field and society?
As we age, our body’s ability to repair and regenerate tissues declines, in large part due to the diminished function of stem cells. In the blood system, this leads to increased vulnerability to infections, inflammatory diseases, and blood cancers. Our research suggests that enhancing the cells’ natural stress-response mechanisms, especially those that manage oxidative stress and cellular clean-up, could help preserve stem cell function during aging. Our findings help to understand how perturbation of cellular homeostasis might lead to disorders or malignancies in hematopoiesis. If we can harness or therapeutically trigger these protective mechanisms, we may be able to slow down the age-associated functional decline of hematopoietic stem cells, potentially delaying or preventing age-related blood disorders. This insight opens the door to devising novel stem cell-based therapies by pre-conditioning cells to better withstand stress and tackle cellular aging before transplantation.
This study provides important mechanistic insights on how organismal aging can potentially impact different organ systems at the cellular level.
What was the exciting moment during your research?
One of the most thrilling moments in this project was realizing that activating the ISR pathway could actually reverse the damaging effects of chronic inflammation in the lymph gland. For a long time, we were observing disrupted hematopoiesis with persistent activation of Toll and Imd pathways, and it genuinely felt like the system was overwhelmed, beyond recovery. There was also a recurring question we faced at conferences: was the increased differentiation of immune cells truly a result of chronic inflammatory stress, or simply a direct consequence of immune pathway overactivation?
That turning point came when we introduced ISR components like Gcn2, or used chemical activators like Histidinol, and suddenly, the differentiation patterns began to normalize. It was a eureka moment. We weren’t just seeing immune activation; we were witnessing a true inflammatory burden on blood progenitors, and the ISR was offering them a way out. It was incredibly satisfying to see our data confirm that even under persistent stress, the system retained a capacity for resilience and repair.
After months of painstaking genetic crosses and protocol optimizations, that sense of scientific clarity and relief was profound. And it’s even more rewarding to think that our tiny fruit flies are helping uncover big ideas about inflammation, aging, and potential interventions in blood-related diseases.
Additionally, presenting this study at a national conference on cell biology via platform presentation in front of a big audience consisting of students, professors, and big-shot scientists from the field and getting inputs and appreciation from them was very rewarding.
Paper reference: Ghosh K*, Iyer RK*, Sood S, Islam MS, Labad JG, Khadilkar RJ. Genetic perturbation of cellular homeostasis regulates Integrated Stress Response signalling to control Drosophila hematopoiesis. Biol Open. 2025 Jun 17: bio.062046. DOI: https://doi.org/10.1242/bio.062046. * indicates equal first authors
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