Not just blood cells; the blood stem cell niche can sense infection

About first author: Parvathy Ramesh is a doctoral student in the laboratory of Dr. Lolitika Mandal at Indian Institute of Science Education and Research (IISER), Mohali. She completed her integrated BS-MS dual degree from IISER, Mohali. Her PhD work mainly involves understanding what it takes to make a stem cell niche using Drosophila larval hematopoietic organ lymph gland as a model system. Here, Parvathy talks about her work “Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection,” recently published in eLife.

How would you explain your paper’s key results to the non-scientific community?

Our body’s immune system is constantly fighting against unwanted guests that use multiple entry points like our nose, mouth, cut in our skin and so on. The blood cells which patrol our body tries to destroy them before these un welcomed guests start multiplying. If they bypass the immune cells by chance, these microorganisms, including bacteria and viruses, can cause infection, and the person will fall sick. During infection, a group of blood cells that serves as the primary defendants called white blood cells (WBCs), are produced on a large scale by the bone marrow. Scientists are still trying to understand the repertoire of signals which drive this transition from the basal to emergency mode of blood cell development.

Employing Drosophila larval blood-forming organ known as the lymph gland, we were able to show one such signaling molecule Relish (Drosophila NF-kB factor), which acts as a joystick between developmental and infection mode of blood cells formation. During development, expression of Relish in the blood stem cell niche helps to maintain blood cells in their naive state. Interestingly, during infection the degradation of Relish pushes the naïve cells towards maturation. As a result, more and more active blood cells are formed, which strengthens the fight against the invaders.

Figure: A. Lymph gland in Drosophila larvae (marked with blue rectangle). B. Enlarged view shows single lobe of lymph
gland. Niche cells send out signals for the maintenance of progenitor cells. During infection, these signals get trapped
in the niche and the progenitor cells undergo precocious differentiation.

we were able to show that the blood stem cell niche is not just a home but can also act as a sensor of the pathophysiological state of the organism.

What are the possible consequences of these findings in your research area?

In the bone marrow, the blood stem cells that can give rise to all types of blood cells, including WBCs are maintained in their ‘naive’ state by the stem cell niche. The bone marrow stem cell niche is composite in nature and has multiple components. The stem cell receives signals from these components, which instructs them to multiply or to differentiate into active blood cells. Hence, niche is considered as the home for stem cells.

Drosophila blood cell repertoire is very similar to the human myeloid lineage. Interestingly, through our study, we were able to show that the blood stem cell niche is not just a home but can also act as a sensor of the pathophysiological state of the organism. In our study, we found that Drosophila hematopoietic niche senses the systemic immune challenge, which results in loss of Relish from the niche. This in turn, diverts normal blood cell formation into emergency mode. It would be exciting to further understand the mechanism through which the hematopoietic niche cells senses the immune challenge.

What was the exciting moment (eureka moment) during your research?

There were many exciting moments. Many challenges came up during the journey, and every time when we came up with an experimental solution, it felt like the eureka moment. One such instance that was an accidental discovery is when we found out that expression of Relish protein in the stem cell niche is down-regulated while we infect the Drosophila larvae. We were not expecting such a dramatic change in its expression since Relish expression is otherwise essential to put up an immune response. This indeed was eureka moment and is one of the significant outcomes of our paper.

What do you hope to do next?

As I mentioned above, we still do not have a complete picture of bone marrow hematopoiesis during pathophysiological challenges. I want to continue working in the field of infection biology where I want to understand how the stem cell niche sense, then respond to external immune challenges, and thereby help the organism fight and survive pathophysiological insults. Studies in this direction can ultimately help us design various stem cell-based therapeutics for blood cell malignancies.

Where do you seek scientific inspiration?

As described by Prof. Richard Feynman, the ‘Pleasure of finding things out’ is the ultimate source of my scientific inspiration. The happiness and the mental satisfaction that we get by simply unravelling a scientific puzzle through experiments is inexpressible. The scientific environment provided to me by my institute (IISER Mohali) and the training and unconditional support provided by my Ph.D. guide Dr. Lolitika Mandal helped me grow up a confident researcher.

How do you intend to help Indian science improve?

India is blessed with a vast number of young minds with a high scientific calibre. According to me, the two most important factors that have to be given utmost importance are growing scientific temperament in students at the early stages of their career and increasing career opportunities in India for researchers. By being a researcher in India, I hope that I could help the scientific community resolve these issues in the future.

From left to right: Aditya Kanwal, Dr.Lolitika Mandal, Parvathy Ramesh

Reference

Ramesh P, Dey NS, Kanwal A, Mandal S, Mandal L. Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection. Elife. 2021 Jul 22;10:e67158. doi: 10.7554/eLife.67158.

Edited by: Nivedita Kamath

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