Modulation of Occluding Junctions Alters the Hematopoietic Niche to Trigger Immune Activation
This week we profile a recent publication in eLife from Rohan Kahdilkar (right) and Dr. Guy Tanentzapf (left) at the University of British Columbia.
Can you provide a brief overview of your lab’s current research focus?
My lab is interested in understanding how cells interact with their environment. In particular, we are interested in the role of cell junctions, which are specialized structures in cells that allow them to interact and communicate with their environment. We are interested in understanding how cell junctions help mediate this sort of interaction and communication in stem cells. Stem cell differentiation and self-renewal are tightly regulated, since producing too many stem cells can result in tumor formation, while producing too many differentiated cells can deplete the stem cell population. Over the last few years my lab has accumulated multiple lines of evidence that occluding junctions, which make tight barriers around tissues, and gap junctions, which form communicating channels between cells, are both very important for stem cell regulation. In my lab we use two main models to study the role of cell junctions: somatic and germline stem cells in the testes, and blood stem cells during hematopoiesis. We use Drosophila as a model organism, because it is well suited to performing complex genetic and imaging experiments, and we have a large array of mutations and other reagents that facilitate the analysis of the role of cell junctions in stem cells.
What is the significance of the findings in this publication?
Our paper reports an important regulatory relationship between occluding junctions and hematopoietic progenitors. We believe, based on the existing literature in the field, that such a relationship is a common conserved feature of many types of stem cells and that our results have important wide-ranging implications. Moreover, our data shows that modulation of occluding junctions provides a previously unreported, and likely conserved, mechanism that links bacterial infection and the activation of hematopoietic stem cells.
The most striking result of our manuscript is showing that the production of immune cells from stem cells in response to infection occurs through a very novel mechanism: the breakdown of a permeability barrier around the hematopoietic stem cell niche that causes an induction of differentiation of blood stem cells.
Briefly, our manuscript describes the existence of a previously uncharacterized, occluding junction-based, permeability barrier in the lymph gland – the primary site of hematopoiesis in Drosophila larva. We demonstrate that upon infection, the permeability barrier disintegrates, altering the signaling environment at the stem cell niche. This change in the microenvironment promotes differentiation of hematopoietic stem cells into immune cells to ensure that these are produced in sufficient numbers to fight a bacterial infection. Importantly, we show that genetic ablation of the permeability barrier is sufficient to activate an immune response and provide protection against bacterial infection. Taken together, our results constitute a novel, previously unreported, general mechanism to regulates stem cell-niche communication and stem cell behaviour.
What are the next steps for this research?
We wish to elucidate the precise ways in which breakdown of the permeability barrier around hematopoietic stem cell niches occurs and the nature of the signals that come into play once the permeability barrier is no longer present. Also since we think the mechanism our paper describes is conserved in other stem cell systems, we wish to explore additional stem cell systems.
This research was funded by:
Our work was funded by the Canadian Institute for Health Research.